2-substituted alkoxy-3-substituted-pyrazines

ABSTRACT

A compound of the formula ##STR1## wherein Q is --CO-- or --CH 2  --, R is hydroxyl, lower alkoxy, halogen, --NH-lower alkylene-OH, --NH-lower alkylene-arylthio, --NH-lower alkylene-halogen, ##STR2## is dilower alkylamino, cycloalkylamino, morpholino, ##STR3## in which R 9  is hydrogen, lower alkyl or aryl, R 10  is hydrogen, lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl or di(aryl)-lower alkyl, m is an integer from 4 to 6, n is 2 or 3, R 1  is alkyl or aryl-lower alkyl, R 2  and R 3  are each lower alkyl, or together form tetramethylene, and R 4  is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof, inhibits blood platelet aggregation, has vasodilating activity and inhibits lipoperoxide generation.

This application is a division of application Ser. No. 07/068,228 filed 6-30-87, now U.S. Pat. No. 4,894,453.

FIELD OF THE INVENTION

This invention relates to novel 2-substituted alkoxy-3-substituted pyrazines, which are useful as pharmaceuticals for treating circulatory and metabolic disorders. The compounds of the invention are active as platelet aggregation inhibiting, vasodilating and/or anti-lipoperoxide generating agents.

KNOWN PRIOR ART

Recently, a significant number of compounds having platelet aggregation inhibiting activity have been reported. Of these, the only known compounds having a pyrazine or 5,6,7,8-tetrahydro quinoxaline ring as the basic structure are tetramethyl pyrazine (16th Heterocyclic Chemistry Symposium (Osaka), pp. 65-68 (1984)) and 2-higher fatty acid acyloxymethyl pyrazine (Jap. Pat. Unexam. Publ. No. 59-219269). Furthermore, a compound of the formula ##STR4## wherein Z is hydrogen or methyl, is known as an α-sympathetic nerve blocking agent (Jap. Pat. Exam. Publ. No. 48-21949). These compounds have almost no platelet aggregation inhibiting, vasodilating or antioxidant activity.

OBJECT OF THE INVENTION

It is an object of the invention to provide high quality pharmaceuticals having stronger inhibitory activities for platelet aggregation, in order effectively to treat circulation and metabolic disorders.

SUMMARY OF THE INVENTION

We have found that 2-substituted alkoxy-3-substituted pyrazines display inhibitory action on platelet aggregation, vasodilation activity and/or anti-lipoperoxide generation, and are expected to have excellent pharmaceutical properties.

According to the present invention, a compound of the formula ##STR5## is provided, wherein Q is --CO-- or --CH₂ --, R is hydroxyl, lower alkoxy, halogen, --NH-lower alkylene-OH, --NH-lower alkylene-arylthio, --NH-lower alkylene-halogen, ##STR6## is dilower alkylamino, cycloalkylamino, morpholino, ##STR7## in which R₉ is hydrogen, lower alkyl or aryl, R₁₀ is hydrogen, lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl or di(aryl)-lower alkyl, m is an integer from 4 to 6, n is 1 or 2, R₁ is alkyl or aryl-lower alkyl, R₂ and R₃ are each lower alkyl, or together form tetramethylene, and R₄ is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof.

Compound [1] can be provided in salt form. The salts must be pharmacologically acceptable non-toxic salt thereof. Examples of such salts are salts of an inorganic acid such as hydrochloric, sulfuric, or phosphoric, and salts of an organic acid such as acetic, propionic, butyric, glycolic, gluconic, malic, tartaric, succinic, mandelic, aspartic, glutamic, methanesulfonic or toluenesulfonic. Salts of other known acids can be used as well.

Compound [1] can be produced by the following processes:

Process A

A process for the production of compound [1] wherein Q is --CO-- and R is lower alkoxy (hereinafter designated as compound [1a]):

The above compound [1a] can be produced by reacting a compound of the formula ##STR8## wherein M is alkali metal, and R₁, R₂ and R₃ have the same meanings hereinbefore, with an α-halogen-carboxylate ester of the formula ##STR9## wherein X is halogen, R₁₁ is lower alkyl and R₄ has the same meaning hereinbefore, in an organic solvent.

The above compound [3] can be obtained by dissolving a compound of the formula ##STR10## wherein R₁, R₂ and R₃ have the same meanings hereinbefore, in methanol containing alkali metal methylate and distilling off methanol in vacuo.

The above compound [2] can be expressed as a tautomer of a compound of the formula ##STR11## wherein R₁, R₂ and R₃ have the same meanings hereinabove.

In compound [2] above, R₁ is alkyl or aryl-lower alkyl. "Alkyl", as used above, is defined as saturated or unsaturated C₁₋₂₀ alkyl, which may be branched or unbranched. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl or hexadecyl, "Optionally substituted phenyl", as used above, is defined as phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro, or lower alkxoy. Aryl-lower alkyl, as used above, is defined as phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy, in which lower alkyl means C₁₋₄ alkyl such as methyl, 1-ethyl, 2-ethyl, 3-propyl or 1-propyl. Examples are benzyl, p-chlorobenzyl, 2-phenylethyl and 1-phenylethyl.

In compound [2] above, R₂ and R₃ are each lower alkyl, or together form tetramethylene. The lower alkyl can be C₁₋₄ alkyl such as methyl, ethyl or propyl. Among the class of compounds [2], some examples have been reported. These compounds can be produced by a process or an improvement thereto as disclosed in J. Am. Chem. Soc., 71:78-81 (1949) and ibid. 74:1580-1583 (1952). Novel derivatives thereof can also be produced according to the methods described in the above references. The compound [2] wherein R₂ and R₃ together form tetramethylene of the formula ##STR12## wherein R₁ has the same meaning hereinabove, hexahydroquinoxaline derivatives, is produced by the process, in which an α-amino acidamide of the formula ##STR13## wherein R₁ has the same meaning hereinabove, is reacted with 1,2-cyclohexanedione in an alkaline medium.

The reaction of the above α-amino acidamide or a salt thereof with 1,2-cyclohexanedione proceeds in an organic solvent, for example a lower alcohol such as methanol or ethanol. The condensation reaction proceeds preferably below 0° C. at first; however, as the reaction proceeds, it can be effected at room temperature. The progress of the reaction can be checked by thin layer chromatography (hereinafter TLC) or high performance liquid chromatography (hereinafter HPLC) and is terminated upon reaching maximum production.

Isolation of the product [2'] can be performed by neutralizing the reaction mixture with an acid such as hydrochloric acid or sulfuric acid, thereafter extracting with water immiscible organic solvent such as chloroform under weakly alkaline conditions, and recrystallizing from an organic solvent such as acetone.

The thus-obtained product [2'] can be purified if necessary, by column chromatography using silica-gel, active alumina or an adsorption resin.

The group R₄ in the above α-halogenocarboxylate ester [4] is defined as hydrogen, lower alkyl or aryl. Examples of lower alkyl are C₁₋₄ alkyls such as methyl, ethyl or propyl, and that of aryl are phenyl optionally substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy.

The group R₉ in the above ester [4] is C₁₋₄ alkyl such as methyl, ethyl or propyl and the group X is halogen, such as chlorine, bromine or iodine.

The reaction of the compound [3] with an α-halogeno carboxylate ester [4] is in general effected in an organic solvent such as dimethylforamide while heating. Isolation of the product [1a] can be performed by distilling off the reaction solvent and extracting the residue with a water-immiscible organic solvent such as benzene chloroform.

Process B

A process for the production of compound [1] wherein Q is --CO-- and R is hydroxyl (hereinafter compound [1b]):

Compound [1b] can be produced by de-esterifying the above compound [1a] by any known de-esterification procedure. For example, compound [1a] is hydrolyzed by alkali hydroxide such as KOH or NaOH, and in case any unreacted compound [1a] remains, after removing the same by extracting with a water-immiscible organic solvent such as chloroform, the reaction mixture is neutralized with an acid and the precipitated product [1b] is filtered or extracted with a water-immiscible organic solvent.

Process C

A process for the production of compound [1] wherein Q is --CO-- and R is --NH-lower alkylene-OH or ##STR14## (hereinafter compound [1c]):

Compound [1c] can be produced by reacting an amine of the formula

    H--R'                                                      [5]

wherein R' is --NH-lower alkylene-OH or ##STR15## is di-lower alkylamino, cycloalkylamino morpholino, ##STR16## wherein R₉, R₁₀, aryl, m and n have the same meanings hereinbefore, with a compound [1b] or its reactive derivatives for N-acylation.

In the group R' in the above amine [5] the lower alkylene moiety is defined as straight or branched C₁₋₄ lower alkylene.

Examples of lower alkylene are methylene, ethylene, methylmethylene, propylene, 1-methylethylene, ethyl-methylene butylene, isobutylene or sec-butylene; C₁₋₃ is preferred.

Di-lower alkylamino in the above ##STR17## is dialkylamino of C₁₋₄ alkyl such as dimethylamino, diethylamino or dipropylamino.

The above cycloalkylamino is cycloalkylamino of C₅₋₈, cycloalkyl such as cyclopentylamino, cyclohexyamino or cycloheptylamino.

The ring ##STR18## in the above ##STR19## wherein m is an integer of 4-6, is defined as pyrrolidine, piperidine or a hexamethyleneimine ring, R₉ means hydrogen, lower alkyl or aryl. "Lower alkyl" means branched or unbranched C₁₋₄ alkyl. "Aryl" as used above means phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy.

The group R₁₀ in the above ##STR20## is defined as hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, hydroxy-lower alkoxy-lower alkyl or di(aryl)-lower alkyl. Examples of the above alkyl are branched or unbranched C₁₋₄ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl. Examples of the above hydroxy-lower alkyl are hydroxyalkyl of C₁₋₄ such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl. Examples of hydroxy-lower alkoxy-lower alkyl are hydroxy alkoxy alkyl comprising alkoxy which is C₁₋₄ lower alkoxy and alkyl which is C₁₋₄ lower alkyl, for example hydroxymethoxymethyl, (2-hydroxyethoxy) methyl, 2-(2-hydroxyethoxy) ethyl or 2-(hydroxymethoxy) ethyl. The group "aryl" in the above di-(aryl)-lower alkyl is phenyl optionally substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy, and the group "lower alkyl" hereinabove is C₁₋₄ alkyl such as methyl or ethyl. An example of di-(aryl)-lower alkyl is diphenylmethyl.

The ring of the group ##STR21## in the above ##STR22## wherein n is 2 or 3, is piperazine or homopiperazine. A lower alkylene bound to the above ring is defined hereinabove and is branched or unbranched C₁₋₄ alkylene.

Examples of aryl are phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy, such as phenyl, tolyl, xylyl, p(m or o)-chlorophenyl, p(m or o)-fluorophenyl, p(m or o)-bromophenyl, 2,4(2,3-, 3,4-, 2,5-, 3,5- or 2,6-)dichlorophenyl, p(m or o)-nitrophenyl, p(m or o)-methoxyphenyl, 2,4(2,3-, 3,4-, 2,5-, 3,5- or 2,6)-dimethoxyphenyl.

Accordingly, specific examples of the amine [5] are dimethylamine, diethylamine, 2-hydroxyethylamine, cyclohexylamine, morpholine, pyrrolidine, piperizine, hexamethyleneimine, 4-methylpiperizine, 4-phenylpiperazine, piperazine, 4-methylpiperazine, 4-ethylpiperazine, 4-propylpiperazine, 4-butylpiperazine, 4-(2-hydroxyethyl)-piperazine, 4-[2-(2-hydroxyethoxy)ethyl]-piperazine, 4-benzylpiperazine, 4-(o-chlorobenzyl)-piperazine, 4-(p-chlorobenzyl)-piperazine, 4-(2,4-dichlorobenzyl)-piperazine, 4-(p-nitrobenzyl)-piperazine, 4-(m-nitrobenzyl)-piperazine, 4-(o-nitrogenzyl)-piperazine, 4-(p-methoxybenzyl)-piperazine, 4-(methylbenzyl)-piperazine, 4-(diphenylmethyl)-piperazine, 4-benzyl-homopiperazine, 4-(p-methylbenzyl)-homopiperazine, 4-(p-chlorobenzyl)-homopiperazine, 4-(p-fluorobenzyl)-homopiperazine, 4-(p-nitrobenzyl)-homopiperazine and 4-(p-methoxybenzyl)-homopiperazine.

The reaction of the above amine [5] and the compound [1b] or its reaction derivative ordinarily proceeds by mixed anhydride method reacting the compound [1b] and amine [5] with pivaloyl chloride in the presence of a tertiary amine such as tetrahydrofuran.

The resulting compound [1f] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent such as benzene or chloroform.

In the above reaction, when piperazine is used as amine [5], a compound [1c], wherein R is ##STR23## in which R₁, R₂, R₃ and R₄ have the same meanings hereinbefore, is produced depending on a ratio of piperazine used.

Process D

A process for the production of the compound [1] wherein Q is --CO-- and R is NH-lower alkylene-halogen (hereinafter compound [1d]):

Compound [1d] can be produced by N-acylating a compound of the formula

    X-lower alkylene-NH.sub.2                                  [6]

wherein X is halogen and lower alkyl has the same meaning hereinabove, with compound [1b] or a reactive derivative thereof.

"Lower alkylene" in the above amine [6] means, as defined hereinbefore, branched or unbranched C₁₋₄ alkylene, such as methylene, ethylene, methylmethylene, propylene, 1-methylethylene, ethylmethylene, butylene, isobutylene or sec-butylene, and --(CH₂)₁₋₃ is preferred.

Examples of the above amine [6] are 2-chloroethylamine and 2-bromoethylamine.

The reaction of the above amine [6] with the compound [1b] or its reactive derivative is performed in the same way as in the process C hereinabove to produce the compound [1d].

Process E

A process for the production of compound [1] wherein Q is --CO-- and R is ##STR24## (hereinafter compound [1e]):

Compound [1e] can be produced by aminating the above compound [1d] with an amino of the formula ##STR25## has the same meaning hereinbefore.

The group ##STR26## in the above amine [7] has the same meaning as ##STR27## as defined in the above amine [5], and the group aryl as defined in the above ##STR28## means phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy.

Examples of amine [7] are the amine [5] hereinbefore and 4-phenylpiperazine, 4-(o-chlorophenyl)-piperazine, 4-(p-chlorophenyl)-piperazine, 4-(p-methoxyphenyl)-piperazine, 4-(m-methoxyphenyl)-piperazine or 4-(m-methoxyphenyl)-piperazine.

The above amination reaction can be effected in an inert organic solvent such as benzene in the presence of a tertiary organic amine such as triethylamine. Isolation of the product [1d] can be performed by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent such as chloroform.

Process F

A process for the production of compound [1] wherein Q is --CH₂ -- and R is --NH-lower alkylene-arylthio (hereinafter compound [1f]):

The above compound [1f] can be produced by thioetherification of the above compound [1d] with aryl-thiol [8].

Aryl in the above aryl-thiol [8] means phenyl or phenyl substituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy, such as thiophenol.

The above thio-etherification can be effected in a reaction solvent such as dimethylformamide in the presence of an alkali such as potassium carbonate or sodium carbonate. Isolation of the compound [1f] can be performed by removing the reaction solvent and extracting with a water-immiscible organic solvent such as chloroform in a dilute aqueous alkali.

Process G

A process for the production for compound [1] wherein Q is --CH₂ -- and R is hydroxyl (hereinafter compound [1g]):

Compound [1g] can be produced by reducing the above compound [1a] with alkali borohydride in lower alcohol with heating.

Isolation of the product [1g] can be performed by removing the organic solvent from the reaction, adding water to the residue and extracting with a water-immiscible organic solvent such as chloroform.

Process H

A process for the production of compound [1] wherein Q is --CH₂ -- and R is halogen (hereinafter compound [1h]):

Compound [1h] can be produced by halogenating the above compound [1g] with a halogenating agent in a reaction solvent.

The said halogenating agent may be any known halogenating agent. Conventional chlorination reagents such as SOCl₂, PCl₅ and POCl₃ can be used. The halogenation reaction can be effected, in general, in an inert organic solvent such as chloroform. The reaction proceeds at room temperature. Isolation of the product [1h] can be performed by adding a water-immiscible organic solvent such as chloroform, washing with dilute aqueous alkali, dehydrating the organic layer and removing the solvent therefrom.

The resulting compound [1h] can be used without purification, as by silica-gel column chromatography, to derive compound [1j] below from compound [1h].

Process J

A process for production of compound [1] wherein Q is --CH₂ -- and R is ##STR29## (hereinafter compound [1j]):

A compound [1j] can be produced by aminating compound [1h] above with the amine [5] in a reaction solvent with heating.

The above amination reaction can be effected in an organic solvent such as benzene with heating

In the above reaction, co-generated acid can be removed by an acid binder, for example a known tertiary organic amine such as triethylamine.

The product [1j] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent such as benzene or chloroform.

The thus-obtained compound [1] is purified, if required, by column chromatography using silica gel, activated alumina or an adsorption resin with an elution solvent such as chloroform-methanol or benzene-ethyl acetate.

A compound [1] is generally produced in the form of its free base, but it can also be produced in the form of a conventional salt thereof. For example, a hydrochloride can be prepared by dissolving a compound [1] in a lower alcohol such as methanol or ethanol, adding a slight molar excess of hydrochloric acid, and isolating the precipitated material, or if not precipitated, by adding ether therein to precipitate the same. The molar ratio of hydrochloric acid may be different according to the specific compound [1].

Examples of the compound [1] of the present invention are set forth in Tables 1 and 2.

                                      TABLE 1     __________________________________________________________________________      ##STR30##     Compound No.             R.sub.1                  R.sub.2                     R.sub.3                        R.sub.4                           Q    R     __________________________________________________________________________     034     Me   Me Me H  CO   OMe     035     Me   Me Me Me CO   OMe     036     Me   Me Me Ph CO   OMe     037     Me   Me Me H  CO   OH     038     Me   Me Me Me CO   OH     039     Me   Me Me Ph CO   OH     066     Me   Me Me H  CO                                 ##STR31##     067     Me   Me Me H  CO                                 ##STR32##     068     Me   Me Me H  CO                                 ##STR33##     069     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2OH     070     Me   Me Me H  CO                                 ##STR34##     071     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2NMe.sub.2     072     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2SPh     073     Me   Me Me H  CO                                 ##STR35##     074     Me   Me Me H  CO                                 ##STR36##     075     Me   Me Me H  CO                                 ##STR37##     076     Me   Me Me H  CO                                 ##STR38##     103     Me   Me Me H  CO                                 ##STR39##     105     Me   Me Me H  CO                                 ##STR40##     135     Me   Me Me H  CO                                 ##STR41##     136     Me   Me Me H  CO                                 ##STR42##     137     Me   Me Me H  CO                                 ##STR43##     341     Et   Me Me Ph CO                                 ##STR44##     342     Et   Me Me Ph CO                                 ##STR45##     343     Et   Me Me Ph CO                                 ##STR46##     344     Et   Me Me Ph CO                                 ##STR47##     345     Et   Me Me Ph CO                                 ##STR48##     346     Et   Me Me Ph CO                                 ##STR49##     347     Et   Me Me Ph CO                                 ##STR50##     348     Et   Me Me Ph CO                                 ##STR51##     376     CH.sub.2 Ph                  Et Et H  CO                                 ##STR52##     377     CH.sub.2 Ph                  Et Et H  CO                                 ##STR53##     379     "    Et Et H  CO                                 ##STR54##     381     "    Et Et H  CO                                 ##STR55##     382     "    Et Et H  CO                                 ##STR56##     491     Et   Me Me H  CH.sub.2                                 ##STR57##     492     Et   Me Me H  CH.sub.2                                 ##STR58##     493     Et   Me Me H  CH.sub.2                                 ##STR59##     494     Et   Me Me H  CH.sub.2                                 ##STR60##     495     Et   Me Me H  CH.sub.2                                 ##STR61##     496     Et   Me Me H  CH.sub.2                                 ##STR62##     497     Et   Me Me H  CH.sub.2                                 ##STR63##     498     Et   Me Me H  CH.sub.2                                 ##STR64##     499     Et   Me Me H  CH.sub.2                                 ##STR65##     500     Et   Me Me H  CH.sub.2                                 ##STR66##     501     Et   Me Me H  CH.sub.2                                 ##STR67##     502     Et   Me Me H  CH.sub.2                                 ##STR68##     503     Et   Me Me H  CH.sub.2                                 ##STR69##     504     Et   Me Me H  CH.sub.2                                 ##STR70##     511     CH.sub.2 Ph                  Me Me H  CH.sub.2                                 ##STR71##     512     "    Me Me H  CH.sub.2                                 ##STR72##     516     "    Me Me H  CH.sub.2                                 ##STR73##     536     Me   Me Me H  CH.sub.2                                 ##STR74##     537     Me   Me Me H  CH.sub.2                                 ##STR75##     538     Me   Me Me H  CH.sub.2                                 ##STR76##     539     Me   Me Me H  CH.sub.2                                 ##STR77##     540     Me   Me Me H  CH.sub.2                                 ##STR78##     541     Me   Me Me H  CH.sub.2                                 ##STR79##     544     iso-Pro                  Me Me H  CH.sub.2                                 ##STR80##     546     "    Me Me H  CH.sub.2                                 ##STR81##     547     "    Me Me H  CH.sub.2                                 ##STR82##     550     "    Et Et H  CH.sub.2                                 ##STR83##     551     "    Et Et H  CH.sub.2                                 ##STR84##     552     iso-Pro                  Et Et H  CH.sub.2                                 ##STR85##     553     "    Et Et H  CH.sub.2                                 ##STR86##     556     iso-Bu                  Et Et H  CH.sub.2                                 ##STR87##     558     "    Et Et H  CH.sub.2                                 ##STR88##     648     Me   Me Me H  CO   NHCH.sub.2 CH.sub. 2Br     649     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2Cl     650     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2C.sub.6 H.sub.11     651     Et   Me Me Ph CO   OMe     652     Et   Me Me Ph CO   OH     653     Et   Me Me Ph CO   NHCH.sub.2 CH.sub.2Cl     654     CH.sub.2 Ph                  Et Et H  CO   OMe     655     "    Et Et H  CO   OH     656     "    Et Et H  CO   NHCH.sub.2 CH.sub.2Cl     657     "    Et Et H  CO                                 ##STR89##     658     "    Et Et H  CO                                 ##STR90##     662     Et   Me Me H  CO   OMe     663     CH.sub.2 Ph                  Me Me H  CO   OMe     664     iso-Pro                  Me Me H  CO   OMe     665     "    Et Et H  CO   OMe     666     iso-Pro                  Et Et H  CO   OMe     679     Me   Me Me H  CH.sub.2                                OH     680     Et   Me Me H  CH.sub.2                                OH     681     CH.sub.2 Ph                  Me Me H  CH.sub.2                                OH     682     iso-Pro                  Me Me H  CH.sub.2                                OH     683     "    Et Et H  CH.sub.2                                OH     684     iso-Bu                  Et Et H  CH.sub.2                                OH     697     iso-Pro                  Me Me H  CH.sub.2                                 ##STR91##     810     Me   Me Me H  CH.sub.2                                 ##STR92##     812     Et   Me Me H  CH.sub.2                                 ##STR93##     814     iso-Pro                  Me Me H  CH.sub.2                                 ##STR94##     822     Me   Me Me H  CH.sub.2                                 ##STR95##     825     iso-Pro                  Me Me H  CH.sub.2                                 ##STR96##     826     iso-Pro                  Et Et H  CH.sub.2                                 ##STR97##     834     iso-Pro                  Me Me H  CH.sub.2                                 ##STR98##     842     Me   Me Me H  CH.sub.2                                NEt.sub.2     844     Et   Me Me H  CH.sub.2                                NEt.sub.2     846     iso-Pro                  Me Me H  CH.sub.2                                NEt.sub.2     848     iso-Pro                  Et Et H  CH.sub.2                                NEt.sub.2     __________________________________________________________________________      Me; methyl      Et; ethyl      Pro; propyl      Bu; butyl      Ph; benzene ring      ( ): position of substituent      ##STR99##      ##STR100##      ##STR101##      ##STR102##

                                      TABLE 2     __________________________________________________________________________      ##STR103##     Compound No.             R.sub.1 Q    R     __________________________________________________________________________     368     CH.sub.2 Ph                     CO                           ##STR104##     369     "       CO                           ##STR105##     370     "       CO                           ##STR106##     371     "       CO                           ##STR107##     372     "       CO                           ##STR108##     373     "       CO                           ##STR109##     517     Bu      CH.sub.2                           ##STR110##     518     Bu      CH.sub.2                           ##STR111##     519     Bu      CH.sub.2                           ##STR112##     520     Bu      CH.sub.2                           ##STR113##     521     Bu      CH.sub.2                           ##STR114##     522     Bu      CH.sub.2                           ##STR115##     559     (CH.sub.2).sub.4 CH.sub.3                     CH.sub.2                           ##STR116##     560     (CH.sub.2).sub.4 CH.sub.3                     CH.sub.2                           ##STR117##     561     "       CH.sub.2                           ##STR118##     562     "       CH.sub.2                           ##STR119##     563     "       CH.sub.2                           ##STR120##     564     (CH.sub.2).sub.5 CH.sub.3                     CH.sub.2                           ##STR121##     565     "       CH.sub.2                           ##STR122##     567     "       CH.sub.2                           ##STR123##     568     "       CH.sub.2                           ##STR124##     569     "       CH.sub.2                           ##STR125##     570     "       CH.sub.2                           ##STR126##     571     (CH.sub.2).sub.6 CH.sub.3                     CH.sub.2                           ##STR127##     572     (CH.sub.2).sub.7 CH.sub.3                     CH.sub.2                           ##STR128##     573     "       CH.sub.2                           ##STR129##     574     "       CH.sub.2                           ##STR130##     575     "       CH.sub.2                           ##STR131##     576     "       CH.sub. 2                           ##STR132##     577     (CH.sub.2).sub.7 CH.sub.3                     CH.sub.2                           ##STR133##     578     "       CH.sub.2                           ##STR134##     579     (CH.sub.2).sub.8 CH.sub.3                     CH.sub.2                           ##STR135##     580     "       CH.sub.2                           ##STR136##     581     "       CH.sub.2                           ##STR137##     582     "       CH.sub.2                           ##STR138##     583     "       CH.sub.2                           ##STR139##     584     "       CH.sub.2                           ##STR140##     585     (CH.sub.2).sub.9 CH.sub.3                     CH.sub.2                           ##STR141##     586     "       CH.sub.2                           ##STR142##     587     "       CH.sub.2                           ##STR143##     588     "       CH.sub.2                           ##STR144##     589     "       CH.sub.2                           ##STR145##     590     "       CH.sub.2                           ##STR146##     591     "       CH.sub.2                           ##STR147##     592     "       CH.sub.2                           ##STR148##     593     (CH.sub.2).sub.9 CH.sub.3                     CH.sub.2                           ##STR149##     594     (CH.sub.2).sub.11 CH.sub.3                     CH.sub.2                           ##STR150##     595     "       CH.sub.2                           ##STR151##     596     "       CH.sub.2                           ##STR152##     597     "       CH.sub.2                           ##STR153##     598     "       CH.sub.2                           ##STR154##     599     "       CH.sub.2                           ##STR155##     600     (CH.sub.2).sub.13 CH.sub.3                     CH.sub.2                           ##STR156##     601     "       CH.sub.2                           ##STR157##     602     "       CH.sub.2                           ##STR158##     603     "       CH.sub.2                           ##STR159##     604     "       CH.sub.2                           ##STR160##     605     "       CH.sub.2                           ##STR161##     606     (CH.sub.2).sub.15 CH.sub.3                     CH.sub.2                           ##STR162##     607     "       CH.sub.2                           ##STR163##     608     "       CH.sub.2                           ##STR164##     609     (CH.sub.2).sub.15 CH.sub.3                     CH.sub.2                           ##STR165##     610     "       CH.sub.2                           ##STR166##     659     CH.sub.2 Ph                     CO   OMe     660     "       CO   OH     661     "       CO   NHCH.sub.2 CH.sub.2Cl     667     Bu      CO   OMe     668     (CH.sub.2).sub.4 CH.sub.3                     CO   OMe     669     (CH.sub.2).sub.5 CH.sub.3                     CO   OMe     670     (CH.sub.2).sub.6 CH.sub.3                     CO   OMe     671     (CH.sub.2).sub.7 CH.sub.3                     CO   OMe     672     (CH.sub. 2).sub.8 CH.sub.3                     CO   OMe     673     (CH.sub.2).sub.9 CH.sub.3                     CO   OMe     674     (CH.sub.2).sub.11 CH.sub.3                     CO   OMe     675     (CH.sub.2).sub.13 CH.sub.3                     CO   OMe     676     (CH.sub.2).sub.15 CH.sub.3                     CO   OMe     677     Pro     CO   OMe     678     sec-Bu  CO   OMe     685     Bu      CH.sub.2                          OH     686     (CH.sub.2).sub.4 CH.sub.3                     CH.sub.2                          OH     687     (CH.sub.2).sub.5 CH.sub.3                     CH.sub.2                          OH     688     (CH.sub.2).sub.6 CH.sub.3                     CH.sub.2                          OH     689     (CH.sub.2).sub.7 CH.sub.3                     CH.sub.2                          OH     690     (CH.sub.2).sub.8 CH.sub.3                     CH.sub.2                          OH     691     (CH.sub.2).sub.9 CH.sub.3                     CH.sub.2                          OH     692     (CH.sub.2).sub.11 CH.sub.3                     CH.sub.2                          OH     693     (CH.sub.2).sub.13 CH.sub.3                     CH.sub.2                          OH     694     (CH.sub.2 ).sub.15 CH.sub.3                     CH.sub.2                          OH     695     Pro     CH.sub.2                          OH     696     sec-Bu  CH.sub.2                          OH     817     Bu      CH.sub.2                           ##STR167##     830     (CH.sub.2).sub.7 CH.sub.3                     CH.sub.2                           ##STR168##     837     Bu      CH.sub.2                           ##STR169##     839     (CH.sub.2).sub.7 CH.sub.3                     CH.sub.2                           ##STR170##     850     Bu      CH.sub.2                          NEt.sub.2     851     (CH.sub.2).sub.7 CH.sub.3                     CH.sub.2                          NEt.sub.2     __________________________________________________________________________      Me; methyl      Et; ethyl      Pro; propyl      Bu; butyl      Ph; benzene ring      ( ): position of substituent      ##STR171##      ##STR172##      ##STR173##      ##STR174##

The pharmacological activity of the present compounds [1] is illustrated below All the compounds [1] used in the pharmacological tests were tested in the form of the hydrochloride salt thereof.

1. Platelet aggregation inhibition

Sample solution containing a compound [1] (final concentration 500 or 100 μM) is added to rabbit platelet plasma to which was added 10% by volume of a 3.8% sodium citrate solution, and the mixture is incubated at 37° C. for 3 minutes. A platelet activation factor (PAF, final concentration 10-50 μg/ml) or collagen (final concentration 2.5 μg/ml) is added thereto as an aggregating agent, and platelet aggregation activity is measured with an aggregometer. The results of assays for PAF-induced aggregation are shown in Table 3, and those for collagen-induced aggregation are shown in Table 4, which tables show the strong platelet aggregation inhibitory activity of the compounds [1] of the present invention.

                  TABLE 3     ______________________________________     Platelet aggregation inhibitory action on PAF-     induced aggregation                   concentration                              inhibition ratio     Compound No.  (μM)    (%)     ______________________________________     560           100        97     561           100        56     562           100        45     565           100        94     567           100        58     570           100        40     571           100        88     573           100        86     580           100        94     587           100        91     588           100        64     595           100        85     600           100        52     067           300        53     070           500        48     135           500        77     136           100        50     137           100        76     341           100        42     342           100        43     344           100        44     347           100        59     348           100        70     502           100        81     503           100        42     504           100        60     541           100        44     550           100        56     551           100        97     552           100        78     553           100        82     556           100        51     ______________________________________

                  TABLE 4     ______________________________________     Platelet aggregation inhibitory action on     collagen-induced aggregation                   concentration                              inhibition ratio     compound No.  (μM)    (%)     ______________________________________     573           100        58     580           100        80     582           100        58     585           100        41     587           100        79     588           100        78     547           100        56     550           100        85     556           100        40     ______________________________________

2. Vasodilation activity

A dog, pretreated with morphine (1.5 mg/kg, sc) is anesthesized with urethane (450 mg/kg, iv) and α-chloralose (45 mg/kg, iv), and immobilized in the dosal position. Right femoral arterial blood is introduced into a left femoral artery via a perfusion pump, and Sterling's resistance is connected to the exosomatic circulatory system to perfuse blood to a left back limb at constant pressure. The perfusion pressure is set at a valve slightly higher than that of the average blood pressure of the animal. Sample (100 μg) dissolved in physiological saline solution is administered to a right femoral artery, and changes in blood flow are measured. Vasodilation activity is measured as a relative activity, by defining as 100% the increased rate of blood flow when 30 μg papaverin is administered intraarterially. The results are shown in Table 5, where it will be seen that the compounds [1] of the present invention have strong vasodilation activity.

                  TABLE 5     ______________________________________     Vasodilation Activity     compound No. vasodilation activity (%)     ______________________________________     075           89     135          242     136          204     137          216     ______________________________________

3. Antioxidant activity

Antioxidant activity is determined according to the method of Stocks et al. [Clin. Sci. Mol. Med., 47: 215 (1974)]. Rat cerebrum is added to ice-cooled 40 mM phosphate saline buffer solution (PBS) (pH 7.4, 4 ml buffer per 1 g cerebrum), homogenized and centrifuged (1000×g, 4° C., 10 min.) to obtain a supernatant solution. The supernatant solution is diluted fivefold with the above ice-cooled PBS solution, and to a 0.9 ml aliquot thereof is added a sample containing a compound [1] (0.1 ml, final concentration 100 μM) dissolved in ethanol. The resultant mixture is incubated at 37° C. for 15 minutes, 35% perchloric acid (0.2 ml) is added, and the mixture is ice-cooled to stop the reaction and centrifuged (1300×g, 4° C., 10 min.). 0.5 ml thiobarbituric acid (5 g/lit. of 50% acetic acid) is added to the supernatant solution (1 ml), so as to measure its absorbancy at 532 nm. The amount of lipoperoxide thus generated is expressed as an amount of malondialdehyde. The results are shown in Table 6, where it will be seen that the compounds [1] of the present invention inhibit lipoperoxide generation.

                  TABLE 6     ______________________________________     Antioxidant activity     compound No.   inhibition ratio (%)     ______________________________________     371            49     372            64     373            49     520            83     562            65     568            61     569            81     570            65     573            56     574            71     575            79     576            85     577            71     578            88     580            77     581            71     582            82     583            82     584            65     585            62     586            68     587            65     588            65     589            74     590            74     591            59     592            85     593            73     594            58     595            70     596            73     597            76     598            88     599            70     600            61     601            67     602            64     603            76     607            52     608            55     609            61     344            48     345            54     347            51     348            62     379            50     382            83     502            69     516            75     ______________________________________

As explained hereinabove, a compound [1] of the present invention or its corresponding salt inhibits platelet aggregation, has-vasodilating activity, and/or inhibits lipoperoxide generation, and is useful in pharmaceutical form for treating circulatory and metabolic disorders.

The following examples are illustrative of the present invention but are not to be construed as limiting.

In the examples, the Rf value of silica-gel thin layer chromatography (TLC) is either specified by or measured using the following carrier and developing solvent:

Carrier: silica gel, Kieselgel 60 F₂₅₄ Art 5715 (Merck)

Developer: chloroform - methanol (20:1)

Physical properties (NMR, Mass, CI, Rf upon TLC) of the compounds [1] obtained in the following examples are shown in Tables 25-27.

Symbols for chemical structure in Tables 7-19 have the same meanings as in Table 1, and the symbols in Tables 20-24 have the same meanings as in Table 2.

EXAMPLE 1

Methyl (3,5,6-trimethylpyrazine-2-yl oxy) acetate (compound 034)

Metallic sodium (1.29 g, 56 mM) was dissolved in anhydrous methanol (120 ml). 2-hydroxy-3,5,6-trimethylpyrazine (7.74 g, 56 mM) was dissolved therein, and methanol was distilled off in vacuo to obtain sodium 3,5,6-trimethyl-2-pyrazinolate which was suspended in dimethylformamide (150 ml). Methyl chloroacetate (10.85 g, 0.10M) was added thereto and the mixture was stirred at 95°-100° C. for 3 hours. The solvent was removed in vacuo. Dilute aqueous sodium carbonate was added to the residue, which was then extracted twice with chloroform (200 ml), and the extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (Wako Pure Chem. Co., C-200, 170 g) and eluted with benzene and benzene-ethyl acetate (10:1) successively to obtain the product. (8.23 g, yield: 70.0%)

EXAMPLE 2

Methyl α-(3,5,6-trimethylpyrazine-2-yl oxy) propionate (compound 035)

Methyl α-chloropropionate (12.25 g, 0.10 mM) was added to sodium 3,5,6-trimethyl-2-pyrazinolate (8.00 g, 50 mM) suspended in dimethylformamide (100 ml) and the mixture was stirred 95°-100° C. for 7 hours. The solvent was distilled off in vacuo. Dilute aqueous sodium carbonate was added to the residue, which was then extracted once with chloroform (200 ml) and twice with chloroform (100 ml), and the extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (Wako Pure Chem. Co., C-200, 160 g) and eluted wtih benzene and benzene-ethyl acetate (10:1) successively to obtain the product. (8.39 g, yield: 74.9%)

EXAMPLE 3

Methyl α-(3,5,6-trimethylpyrazine-2-yl oxy) phenyl acetate (compound 036)

Methyl α-bromophenyl acetate (23.0 g, 0.10 mM) was added to sodium 3,5,6-trimethyl-2-pyrazinolate (8.00 g, 50 mM) suspended in dimethylformamide (150 ml) and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was treated in the same way as in Example 2 to obtain the product. (10.97 g, yield: 76.7%)

EXAMPLE 4

(3,5,6-trimethylpyrazine-2-yl oxy) acetate (compound 037)

Aqueous 1N-NaOH (80 ml) was added to compound 034 (8.40 g, 40 mM) and the mixture was stirred for 30 minutes. 1N-HCl (80 ml) was added to the reaction mixture and the precipitated crystals were collected by filtration to obtain a portion of the product. (3.15 g) The filtrate was dried in vacuo and the residue was extracted with hot ethanol, then the extract was dried in vacuo to obtain the remainder of the product. (4.09 g) (Total: 7.24 g, yield: 92.3%)

EXAMPLE 5

α-(3,5,6-trimethylpyrazine-2-yl oxy) propionate (compound 038)

Aqueous 1N-NaOH (80 ml) was added to compound 035 (7.81 g, 35 mM) and the mixture was stirred for 1 hour. The reaction mixture was extracted with chloroform to remove unreacted compound. 1N-HCl (70 ml) was added to the aqueous layer and the mixture was concentrated in vacuo to precipitate crystals, which were collected by filtration, washed with water completely and dried to obtain the product. (6.66 g, yield: 90.6%)

EXAMPLE 6

α-(3,5,6-trimethylpyrazine-2-yl oxy) phenyl acetate (compound 039)

Aqueous 1N-NaOH (75 ml) was added to compound 0.36 (10.80 g, 37.7 mM) dissolved in methanol (75 ml) and the mixture was stirred for 1.5 hour. Methanol was distilled off in vacuo and the aqueous layer was washed with chloroform. 1N-HCl (75 ml) was added to the aqueous layer which was extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo to obtain the product as white crystals. (9.89 g, yield: 96.4%

EXAMPLES 7-12

2-(substituted carbonylmethoxy)-3,5,6-trimethylpyrazine

Triethylamine (0.70 ml, 5 mM) was added to compound 037 (0.98 g, 5 mM) dissolved in tetrahydrofuran Pivaloyl chloride (0.16 g, 5 mM) was added dropwise at -5° C. and the mixture was stirred for 30 minutes with ice cooling. A tetrahydrofuran solution of a base (5 mM) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was dried with chloroform, then concentrated in vacuo. The residue was charged on a column of silica gel (C-20, 60 g) and eluted with chloroform and chloroform-methanol (200:1) successively to obtain the compounds in Table 7.

Table 7 identifies the product, yields in weight and percentage, the base and its amount used.

EXAMPLE 13

N-(2-bromoethyl)-3,5,6-trimethylpyrazine-2-yl oxy) acetamide (compound 648)

Triethylamine (7.0 ml, 50 mM) was added to compound 037 (9.80 g, 50 mM) dissolved in tetrahydrofuran (100 ml) and chloroform (100 ml) in solution with bromoethylamine hydrobromide (10.30 g, 50 mM) and triethylamine (7.7 ml, 55 mM) was added dropwise at -5° C., then the mixture was stirred for 4 hours with ice cooling. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was extracted with chloroform. The organic layer was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (Chlodil, 250 g), and eluted successively with chloroform and chloroform-methanol (500:1) to obtain the product (6.92 g)

EXAMPLE 14

N-(2-chloroethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide (compound 649)

Triethylamine (3.50 ml, 25 mM) was added to compound 037 (4.90 g, 25 mM) dissolved in tetrahydrofuran (50 ml) and pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C., then the mixture was stirred for 30 mintes. Chloroform (50 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g, 25 mM) and triethylamine (3.9 ml, 28 mM) was added dropwise thereto, then the mixture was stirred for 4 hours while slowly reaching room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was extracted with chloroform. The organic layer was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 40 g), and eluted successively with chloroform and chloroform-methanol (20:1) to obtain the product (5.66 g, yield: 7.5%)

EXAMPLES 15-21

N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide:

Benzene (20 ml) in solution with compound 648 (0.91 g, 3.0 mM), triethylamine (0.84 ml) and a base was refluxed. The reaction mixture was washed with dilute aqueous potassium carbonate, and the aqueous layer was extracted with chloroform. The organic layers (benzene and chloroform) was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 65 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 8.

Table 8 shows the reflux time, yield in weight and percentage, the base and its amount used and the ratio of chloroform-methanol mixture used in each of the above examples.

EXAMPLE 22

N-(2-phenylthioethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide (compound 072)

Thiophenol (0.60 g, 5.4 mM) and potassium carbonate (0.75 g, 5.4 mM) were added to compound 648 (0.91 g, 3.0 mM) dissolved in dimethylformamide (10 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was further extracted with chloroform. The combined organic layer was chromatographed by eluting successively with benzene and benzene-ethyl acetate (10:1) to obtain the product (0.35 g, yield: 35.2%)

EXAMPLES 23-25

N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide

Benzene (25 ml) in solution with compound 649 (0.98 g, 4 mM), triethylamine (1.14 ml) and a base was refluxed. The reaction mixture was washed with dilute aqueous potassium carbonate, and the aqueous layer was further extracted with chloroform. The organic layers (benzene and chloroform) were combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 80 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 9.

Table 9 shows the identity of the base and its amount used, the reflux time, the ratio of chloroform-methanol mixture used, the products and the yield in weight and percentage, in each of the above examples.

EXAMPLE 26

Methyl α-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetate (compound 651)

A solution (12.5 ml) of 4N-CH₃ ONa/methanol was added to a solution of 2-hydroxy-3-ethyl-5,6-dimenthylpyrazine (7.60 g, 50 mM) in anhydrous methanol (100 ml), and methanol was distilled off in vacuo. The residue was dissolved in dimethylformamide (150 ml). Methyl α-bromophenyl acetate (11.5 g, 50 mM) was added thereto, and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform, and washed with dilute aqueous potassium carbonate. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 170 g) and eluted successively with benzene and benzene-ethyl acetate (50:1) to obtain the product (10.42 g, yield 69.5%)

EXAMPLE 27 α-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetate (compound 652):

Aqueous 2N-NaOH (25.7 ml) was added to compound 651 (7.72 g, 25.7 mM) dissolved in methanol (30 ml) and the mixture was stirred for 4.5 hours at room temperature. The reaction mixture, to which 2N-HCl (25.7 ml) was added, was ice cooled to precipitate crystals. The thus-precipitated crystals were collected by filtration, washed with water and dried to obtain the product (6.91 g, yield: 94.0%)

EXAMPLE 28

N-(2-chloroethyl)-α-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetamide (compound 653)

Triethylamine (3.7 ml, 26.6 mM) was added to compound 652 (7.50 g, 26.2 mM) dissolved in tetrahydrofuran (44 ml) and pivaloylchloride (3.21 g, 26.3 mM) was added dropwise at -5° C., then the mixture was stirred for 30 minutes. Chloroform (26 ml) in solution with 2-chloroethylamine hydrochloride (3.05 g, 26.3 mM) and triethylamine (3.7 ml) was added dropwise thereto with cooling at 0°-5° C., then the mixture was stirred for 1 hour with ice cooling and for 4 hours at room temperature. Chloroform was added to the reaction mixture and the mixture was washed with dilute aqueous potassium carbonate. The aqueous layer was further extracted twice with chloroform. The organic layer were combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 170 g), and eluted successively with benzene, benzene-ethyl acetate (40:1) and benzene-ethyl acetate (10:1) to obtain the product (6.46 g, yield 70.4%)

EXAMPLES 29-36

N-(2-substituted ethyl)-α-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetamide

A base (8.0 mM) was added to benzene (30 ml) in solution with compound 653 (1.39 g, 4.0 mM) and triethylamine (1.12 ml) and the mixture was refluxed overnight. The reaction mixture was washed with dilute aqueous potassium carbonate, and the aqueous layer was further extracted three times with chloroform. The organic layers (benzene and chloroform) were combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 65 g) and eluted successively with chloroform and chloroform-methanol (100:1) to obtain the compounds in Table 10.

Table 10 shows the identity of the base and its amount used, the compounds and their yield in weight and percentage in each of the above examples.

EXAMPLE 37

Methyl (3-benzyl-5,6-diethylpyrazine-2-yl oxy) acetate (compound 654)

A solution of 4N-CH₃ ONa/methanol (10.0 ml, 40 mM) was added to a solution of 2-hydroxy-3-benzyl-5,6-diethylpyrazine (9.68 g, 40 mM) in anhydrous methanol (120 ml), and methanol was distilled off in vacuo. The residue was dissolved in dimethylformamide (150 ml). Methyl chloroacetate (4.34 g, 40 mM) was added thereto, and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was concentrated in vacuo, diluted aqueous potassium carbonate was added to the residue and the aqueous layer was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 170 g) and eluted successively with benzene and benzene-ethyl acetate (100:1) to obtain the product. (11.41 g, yield: 90.8%)

EXAMPLE 38

(3-benzyl-5,6-diethylpyrazine-2-yl oxy) acetate (compound 655)

Aqueous 2N-NaOH (34 ml) was added to compound 954 (10.68 g, 34.0 mM) dissolved in methanol (34 ml) and the mixture was stirred for 3 hours. 2N-HCl (34 ml) was added to the reaction mixture and the precipitated crystals were collected by filtration, washed completely with water and dried to obtain the product. (8.86 g, yield: 86.9%)

EXAMPLE 39

N-(2-chloroethyl)-(3-benzyl-5,6-diethylpyrazine-2-yl oxy) acetamide (compound 656)

Pivaloyl chloride (3.66 g, 30 mM) was added dropwise at -5° C. to compound 655 (8.62 g, 28.7 mM) and triethylamine (4.2 ml, 30 mM) dissolved in tetrahydrofuran (50 ml), then the mixture was stirred for 30 minutes. Chloroform (30 ml) in solution with 2-fluoroethylamine hydrochloride (3.48 g) and triethylamine (4.2 ml) was added dropwise thereto with cooling at 0° to -5° C. then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate (5:1) to obtain the product. (9.21 g, yield: 88.8%)

EXAMPLES 40-46

N-(2-substituted ethyl)-(3-benzyl-5,6-dimethylpyrazine-2-yl oxy) acetamide

Benzene (30 ml) in solution with compound 656 (1.27 g, 3.5 mM), triethylamine (0.98 ml, 7 mM) and a base (7 mM) was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The organic layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 80 g) and eluted successively with chloroform and chloroform-methanol (100:1) to obtain the compounds in Table 11.

Table 11 shows the identity of the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 47-51

Methyl (3,5,6-trialkylpyrazine-2-yl oxy) acetate

Metallic sodium (1.15 g) was dissolved in anhydrous methanol (100 ml). A starting material 2-hydroxy-3,5,6-trialkylpyrazine (50 mM) was dissolved therein, and methanol was distilled off in vacuo to obtain the sodium salt thereof. Dimethylformamide (100 ml) and methyl chloroacetate (5.43 g, 50 mM) were added thereto, then the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200) and eluted successively with benzene and benzene-ethyl acetate (20:1) to obtain the compounds in Table 12.

Table 12 shows the identity of the starting compound and its amount used, the reaction time, the amount of silica gel used and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 52-57

2-(2-hydroxyethoxy)-3,5,6-trialkylpyrazine

A starting compound was dissolved in methanol 6-8 equivalents of NaBH4 were added stepwise while refluxing. The reaction mixture was concentrated in vacuo, water was added thereto, then the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200) and eluted successively with benzene and benzene-ethyl acetate (10:1) to obtain the compounds in Table 13.

Table 13 shows the identity of the starting compound and its amount used, the amount of NaBH₄ used, the reflux time, the amount of silica gel used and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 58-66

2-(2-substituted ethoxy)-3,5,6-trimethylpyrazine

Thionyl chloride (0.56 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 679 (1.10 g, 6.0 mM) dissolved in chloroform and the mixture was stirred at room temperature for 2.5 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.68 ml, 12 mM) and a base (12 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol (200:1) to obtain the compounds in Table 14.

Table 14 shows the identity of the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 67-72

2-(2-substituted ethoxy)-3-isopropyl-5,6-diethylpyrazine

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 683 (1.19 g, 5.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 4 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol (200:1) to obtain the compounds in Table 15.

Table 15 shows the identity of the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 73-88

2-(2-substituted ethoxy)-3-ethyl-5,6-dimethylpyrazine

Thionyl chloride (0.43 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 680 (0.98 g, 5.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 3 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (60 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200 75 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 16.

Table 16 shows the identity of the base and its amount used, the reflux time, the ratio of chloroform-methanol in the column chromatography, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 89-91

2-(2-substituted ethoxy)-3-benzyl-5,6-dimethylpyrazine:

Thionyl chloride (0.36 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 681 (1.04 g, 4.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 3 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (8.0 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 17.

Table 17 shows the identity of the base and its amount used, the reflux time, ratio of chloroform-methanol in column chromatography, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 92-98 2-(2-substituted ethoxy)-3-isopropyl-5,6-dimethylpyrazine

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 682 (1.05 g, 4.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 3.5 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 18.

Table 18 shows the identity of the base and its amount used, the reflux time, the ratio of chloroform-methanol in the column chromatography, and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 99-100 2-(2-substituted ethoxy)-3-isobutyl-5,6-diethylpyrazine:

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with ice cooling to compound 684 (1.26 g, 5.0 mM) dissolved in chloroform (5 ml) and the mixture was stirred at room temperature for 4 hours. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) were added to the residue, and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol to obtain the compounds in Table 19.

Table 19 shows the identity of the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

Comparative Example 1 2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline:

A methanol (30 ml) solution of cyclohexane-1,2-dione (13.44 g, 0.12 M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1 M) dissolved in methanol (200

ml) with cooling below -30° C., and aqueous 12.5 N-NaOH (20 ml) was added dropwise thereto. The reaction mixture was 1 stirred at below -30° C. for 30 minutes and was further stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture, and sodium bicarbonate (15 g) was added after 10 minutes stirring, the solvent then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the product. (19.7 g, yield: 82.1%)

COMPARATIVE EXAMPLE 2 2-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydroquinoxaline:

A methanol (20 ml) solution of cyclohexane-1,2-dione (5.38 g) was added to o-amino-2-phenylacetic acidamide hydrochloride (8.58 g, 40 mM) dissolved in methanol (100 ml) with cooling below -30° C., and aqueous 12.5 N-NaOH was added dropwise thereto. The reaction mixture was stirred at below -30° C. for 30 minutes, and the mixture was stirred at room temperature for 6 hours. Conc. hydrochloric acid (8 ml) was added to the reaction mixture, and sodium bicarbonate (6.0 g) was added after 10 minutes stirring, the solvent then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the product. (6.79 g, yield: 66.8%)

COMPARATIVE EXAMPLE 3

2-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoxaline:

A methanol (20 ml) solution of cyclohexane-1,2-dione (6.72 9) was added to alanine (4.4 g, 50 mM) dissolved in methanol (100 ml) with cooling below -30° C., and aqueous 12.5 N-NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred at below -30° C. for 30 minutes, and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (8 ml) was added to the reaction mixture, and sodium bicarbonate (5 g) was added after 10 minutes stirring, the solvent then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the product as pale yellowish crystals. (6.50 g, yield: 79.0%)

COMPARTIVE EXAMPLE 4

2-hydroxy-3-ethyl-5,6,7,8-tetrahydroquinoxaline:

A methanol (20 ml) solution of cyclohexane-1,2-dione (6.72 g, 60 mM) was added to a methanol solution (100 ml) of α-aminobutylamide (5.1 g, 50 mM) with cooling below -30° C., and aqueous 12.5 N-NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred at below -30° C. for 30 mins. and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (6.25 ml) was added to the reaction mixture and sodium bicarbonate (5 g) was added after 10 minutes stirring, the solvent being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the colorless crystals. (5.30 gm, yield: 60.0%)

COMPARATIVE EXAMPLES 5-

2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline:

Cyclohexane-1,2-dione (6.72 g, 60 mM) was added a 11 at once to amino acidamine hydrochloride (50 mM) dissolved in methanol (100 ml) with cooling below -30° C., and aqueous 12 N-NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred for 30 minutes with cooling below -30° C., and the mixture was stirred at room temperature for 5 hours. Conc. hydrochloric acid (12.5 ml) was added to the reaction mixture and sodium bicarbonate (7.5 g) was added after 10 minutes, whereafter the solvent was distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the products shown in Table 20.

Table 20 shows the identity of the acid amide hydrochloride and its amount used and the product and yield in weight and percentage in each of the above comparative examples.

EXAMPLE 101

Methyl (3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetate (compound 656):

2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline (12.0 g, 50 mM) was dissolved in a solution of metallic sodium (1.15 g, 50 mM) in anhydrous methanol (200 ml), whereafter methanol was distilled off in vacuo to obtain the sodium salt thereof, which was suspended in dimethylformamide (100 ml). Methyl chloroacetate (5.43 g, 50 mM) was added thereto and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated in vacuo. Dilute aqueous sodium carbonate was added to the residue, which was then extracted three times with chloroform, and the extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charge on a column of silica gel (C-200, 180 g) and eluted successively with benzene and benzene-ethyl acetate (10:1) to obtain the product. (14.12 g, yield: 90.5%)

EXAMPLE 102

(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetate (compound 660):

Aqueous 2N-NaOH (30 ml) was added to compound 656 (9.42 g, 30.2 mM) dissolved in methanol (30 ml) and the mixture was stirred for 3 hours at room temperature. 2N-HCl (30 ml) was added to the reaction on mixture with ice cooling and the precipitated crystals were collected by filtration, washed with water and dried to obtain most of the product. (8.10 g) The filtrate was concentrated in vacuo and the residue was extracted with hot ethanol, then the extract was concentrated in vacuo. The residue dissolved in dilute aqueous NaOH, was neutralized with 1 N-HCl and the precipitated crystals were collected by filtration, washed with water, then dried to obtain the remainder of the product. (0.32 g) (Total: 8.42 g, yield: 93.6%)

EXAMPLE 103

N-(2-chloroethyl)-(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetamide (compound 661):

Pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C. to compound 660 (7.45 g, 25 mM) and triethylamine (3.5 ml, 25 mM) dissolved in tetrahydrofuran (45 ml), then the mixture was stirred for 30 minutes. Chloroform (25 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g) and triethylamine (3.5 ml) was added dropwise thereto, then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate to obtain the product. (7.142 g, yield: 79.5%)

EXAMPLES 104-109

N-(2-substituted ethyl)-(3-benzyl-5,6,7,8-tetra-hydroquinoxaline-2-yl oxy) acetamide:

Benzene (30 ml) in solution with compound 661(1.08 g, 3.0 mM), triethylamine (0.84 m) and a base (6.0 mM) was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture, and the aqueous layer was extracted three times with chloroform. The organic layer was dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 80 g) and eluted successively with benzene and benzene-ethyl acetate (10:1) to obtain the compounds in Table 21.

Table 21 shows the identity of the base and its amount used, the reflux time, the products and the yield in weight and percentage, in each of the above examples. Examples 110-121

Methyl (3-alkyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetate:

Metallic sodium (1.15 g) was dissolved in anhydrous methanol (100 ml). 2-hydroxy-3,-alkyl-5,6,7,8-tetrahydroquinoxaline (50 mM) was dissolved therein, and methanol was distilled off in vacuo to obtain the sodium salt. Dimethylformamide (100 ml) and methyl chloroacetate (5.43 g, 50 mM) were added thereto and the mixture was stirred at 100° C. The reaction mixture was concentrated in vacuo, and dilute aqueous sodium carbonate was added to the residue, which was then extracted three times with chloroform, and the extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200) and eluted successively with benzene and benzene-ethyl acetate- (20:1) to obtain the compounds in Table 22.

Table 22 shows the identity of the starting compound and its amount used, the reaction time, the amount of silica gel used, the products and the yield in weight and percentage in each of the above examples.

EXAMPLES 122-123

2-(2-hydroxyethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline:

The starting compound was dissolved in methanol. 6-8 equivalents of NaBH4 were added several portionwise while refluxing. The reaction mixture was concentrated in vacuo, water was added thereto, then the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200) and eluted successively with benzene and benzene-ethyl acetate (10:1) to obtain the compounds in Table 23.

Table 23 shows the identity of the starting compound and its amount used, the amount of methanol used, the amount of NaBH₄ used, the reflux time, the amount of silica gel used and the product and yield in weight and percentage in each of the above examples.

EXAMPLES 134-185

2-(2-substituted ethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline:

Thionyl chloride (1.3 equivalent) was added dropwise with ice cooling to a starting compound 2-(2-hydroxy- ethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline (3-5 mM) dissolved in chloroform and the mixture was stirred at room temperature for 2.5 hours to chlorinate the compound. The reaction mixture was poured into dilute aqueous potassium carbonate and extracted three times with chloroform. The extract, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (2 equivalents) and a base (2 equivalents) were added to the residue, and the mixture was refluxed. The reaction mixture was poured into dilute aqueous potassium carbonate, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 75 g) and eluted successively with chloroform and chloroform-methanol (200:1) to obtain the compounds in Table 24.

Table 24 shows the identity of the starting compound and its amount used, the chlorination reaction time, the base and its amount used, the reflux time, and the product and yield in weight and percentage in each of the above examples.

                                      TABLE 7     __________________________________________________________________________     2-(substituted carbonylmethoxy)-3,5,6-trimethylpyrazine     Base                         Yield                                      Yield     Example          name          used (g)                             Product                                  (g) (%)     __________________________________________________________________________           ##STR175##   0.50 066  1.12                                      80.5     8           ##STR176##   0.43 067  1.10                                      83.6     9           ##STR177##   0.66 068  1.23                                      79.8     10   H.sub.2 NCH.sub.2 CH.sub.2OH                        0.32 069  0.88                                      73.6     11           ##STR178##   0.43 070  0.91                                      82.0     12           ##STR179##   0.44 075  1.10                                      83.0     __________________________________________________________________________      Product is shown by No. of compound

                                      TABLE 8     __________________________________________________________________________     N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yloxy)acetamide                                      solvent     Base                        reaction                                      ratio    Yield                                                   Yield     Example          name            used (g)                                 (time)                                      (hr.)                                          product                                               (g) (%)     __________________________________________________________________________     15   40% HN (CH.sub.3).sub.2 aqueous solution                          8.68   1    50:1                                          071  0.22                                                   27.6     16           ##STR180##     0.53 (6 mM)                                 1.5  100:1                                          073  0.41                                                   44.4     17           ##STR181##     0.43 (5 mM)                                 1    20:1                                          074  0.55                                                   59.9     18           ##STR182##     0.78 (6 mM)                                 1.5  50:1                                          076  0.58                                                   55.0     19           ##STR183##     3.44 (40 mM)                                 1.5  10:1                                          103  0.94                                                   30.0     20           ##STR184##     0.60 (6 mM)                                 1    50:1                                          105  0.27                                                   28.0     21   H.sub.2 NC.sub.6 H.sub. 11                          0.60 (6 mM)                                 1.5  50:1                                          650  0.17                                                   17.7     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 9     __________________________________________________________________________     N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yloxy)acetamide                               reaction     BASE                      time solvent  Yield                                                 Yield     Example          name           used (g)                               (hr.)                                    ratio                                        Product                                             (g) (%)     __________________________________________________________________________     23           ##STR185##    1.68 (8 mM)                               8    100:1                                        135  0.50                                                 30.5     24           ##STR186##    1.41 (8 mM)                               6     50:1                                        136  0.43                                                 27.1     25           ##STR187##    1.68 (8 mM)                               8    100:1                                        137  0.50                                                 30.5     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 10     __________________________________________________________________________     N(2-substituted ethyl)-α -(3-ethyl-5,6-dimethylpyrazine-2-yloxy)-phe     nylacetamide     BASE                          Yield                                       Yield     Example          name           used (g)                              product                                   (g) (%)     __________________________________________________________________________     29           ##STR188##    0.70 341  0.94                                       59.0     30           ##STR189##    1.41 342  1.48                                       76.0     31           ##STR190##    1.69 343  1.27                                       60.9     32           ##STR191##    1.77 344  1.32                                       62.0     33           ##STR192##    1.96 345  0.91                                       41.0     34           ##STR193##    1.30 346  1.20                                       63.4     35           ##STR194##    1.67 347  1.28                                       61.5     36           ##STR195##    1.80 348  1.77                                       82.6     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 11     __________________________________________________________________________     N-(2-substituted ethyl)-(3-benzyl-5,6-dimethylpyrazine-2-yloxy)-acetamide     BASE                     reaction  Yield                                            Yield     Example          name           used (g)                              (day)                                   product                                        (g) (%)     __________________________________________________________________________     40           ##STR196##    1.24 2    376  1.54                                            87.8     41           ##STR197##    1.48 2    377  1.48                                            81.5     42           ##STR198##    1.48 2    379  1.17                                            62.4     43           ##STR199##    1.38 1    381  1.29                                            70.7     44           ##STR200##    1.58 2    382  1.38                                            71.8     45           ##STR201##    0.61 2    657  0.73                                            50.6     46           ##STR202##    1.14 1    658  1.15                                            67.6     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 12     __________________________________________________________________________     methyl(3,5,6-trialkylpyrazine-2-yloxy)-acetate     starting material     R.sub.3 N OH       reaction     R.sub.2 N R.sub.1                     used                        time silica-gel                                       Yield                                           Yield     Example          R.sub.1               R.sub.2                  R.sub.3                     (g)                        (hr.)                             (g)  product                                       (g) (%)     __________________________________________________________________________     47   Et   Me Me 7.60                        2.5  160  662  9.62                                           85.9     48   --CH.sub.2 Ph               Me Me 10.70                        2.5  210  663  12.03                                           84.1     49   iso-Pro               Me Me 8.3                        2.5  160  664  9.92                                           83.4     50     "  Et Et 9.70                        2.5  180  665  12.77                                           96.0     51   iso-Bu               Et Et 10.40                        3    230  666  12.86                                           91.9     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 13     __________________________________________________________________________     2-(2-hydroxyethoxy)-3,5,6-trialkylpyrazine                             reaction     starting material                    methanol                         NaBH.sub.4                             time silica-gel                                            Yield                                                Yield     Example          name             used g (mM)                    (ml) (g) (hr.)                                  (g)  product                                            (g) (%)     __________________________________________________________________________     52   034             17.00(80.95)                    200  18.6                             3.0  200  679  12.84                                                87.2     53   662             9.62(42.94)                    200  9.9 4.0  120  680  7.69                                                91.3     54   663             8.75(30.6)                    150  9.4 2.5  160  681  7.22                                                91.5     55   664             19.67(82.65)                    200  25.2                             3.0  200  682  15.51                                                89.4     56   665             9.18(34.5)                    150  10.5                             4.0  200  683  7.48                                                91.1     57   666             7.32(26.14)                    100  8.0 3.5  160  684  5.94                                                90.1     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 14     __________________________________________________________________________     2-(2-substituted ethoxy)-3,5,6-trimethylpyrazine                               reaction     BASE                      time      Yield                                             Yield     Example          name            used (g)                               (hr.)                                    product                                         (g) (%)     __________________________________________________________________________     58           ##STR203##     1.05 2.5  536  0.95                                             63.1     59           ##STR204##     1.10 2.5  537  1.03                                             68.9     60           ##STR205##     2.02 3.0  538  1.31                                             64.2     61           ##STR206##     2.11 2.5  539  1.62                                             72.1     62           ##STR207##     1.94 2.0  540  1.59                                             74.0     63           ##STR208##     2.25 2.5  541  1.56                                             66.9     64           ##STR209##     1.70 5.0  810  1.28                                             70.0     65           ##STR210##     3.90 5.0  822  1.56                                             94.5     66   HNEt.sub.2      0.88 5.0  842  0.51                                             35.7     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 15     __________________________________________________________________________     2-(2-substituted ethoxy)-3-isopropyl-5,6-diethylpyrazine                                reaction     BASE                       time      Yield                                              Yield     Example          name             used (g)                                (hr.)                                     product                                          (g) (%)     __________________________________________________________________________     67           ##STR211##      0.85 3.0  550  0.83                                              54.4     68           ##STR212##      1.42 2.5  551  0.93                                              51.4     69           ##STR213##      1.76 3.0  552  1.05                                              52.8     70           ##STR214##      2.20 3.0  553  1.01                                              46.0     71           ##STR215##      1.30 5.0  826  1.15                                              66.2     72   HNEt.sub.2       0.73 6.5  848  0.36                                              25.2     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 16     __________________________________________________________________________     2-(2-substituted ethoxy)-3-ethyl-5,6-dimethylpyrazine     Base                            reaction                                          solvent  Yield                                                       Yield     Example          name                  used (g)                                     time (hr.)                                          ratio                                              product                                                   (g) (%)     __________________________________________________________________________     73           ##STR216##           0.87 2.5  200:1                                              491  0.66                                                       49.8     74           ##STR217##           0.85 2.0  200:1                                              492  0.79                                                       60.1     75           ##STR218##           1.00 2.0  200:1                                              493  0.67                                                       48.4     76           ##STR219##           1.00 2.0   30:1                                              494  0.84                                                       44.6     77           ##STR220##           1.20 2.0  100:1 →  10:1                                              495  0.73                                                       47.4     78           ##STR221##           1.74 2.0   50:1                                              496  1.13                                                       64.2     79           ##STR222##           1.68 2.0  200:1                                              497  1.15                                                       65.0     80           ##STR223##           2.11 2.0  200:1                                              498  1.10                                                       56.6     81           ##STR224##           2.06 2.0  200:1                                              499  1.17                                                       60.9     82           ##STR225##           1.94 2.0  200:1                                              500  1.17                                                       62.9     83           ##STR226##           2.21 2.0  200:1                                              501  1.40                                                       70.2     84           ##STR227##           2.35 2.0  200:1                                              502  0.62                                                       30.0     85           ##STR228##           2.08 2.0  200:1                                              503  1.00                                                       51.8     86           ##STR229##           2.25 2.0  200:1                                              504  1.14                                                       56.6     87           ##STR230##           1.42 2.0  200:1                                              812  0.67                                                       42.0     88   HNEt.sub.2            0.73 3.0  200:1                                              844  0.23                                                       18.8     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 17     __________________________________________________________________________     2-(2-substituted ethoxy)-3-benzyl-5,6-dimethylpyrazine     Base                            reaction                                          solvent  Yield                                                       Yield     Example          name                  used (g)                                     time (hr.)                                          ratio                                              product                                                   (g) (%)     __________________________________________________________________________     89           ##STR231##           0.70 2.0  200:1                                              511  0.57                                                       43.6     90           ##STR232##           1.04 2.0  200:1                                              512  1.04                                                       62.5     91           ##STR233##           1.80 2.0  200:1                                              516  1.20                                                       64.6     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 18     __________________________________________________________________________     2-(2-substituted ethoxy)-3-isopropyl-5,6-dimethylpyrazine                               reaction     BASE                      time solvent  Yield                                                 Yield     Example          name            used (g)                               (hr.)                                    ratio                                        product                                             (g) (%)     __________________________________________________________________________     92           ##STR234##     0.87 2.5  200:1                                        544  0.89                                                 63.8     93           ##STR235##     2.11 2.5  200:1                                        546  1.57                                                 80.8     94           ##STR236##     2.25 2.5  200:1                                        547  1.42                                                 68.2     95           ##STR237##     1.43 3.0  200:1                                        697  0.94                                                 56.3     96           ##STR238##     1.43 2.0  200:1                                        814  0.77                                                 46.0     97           ##STR239##     1.30 2.5  200:1                                        825  1.24                                                 77.0     98           ##STR240##     0.85 5.0  200:1                                        834  1.17                                                 68.3     99   HNEt.sub.2      0.73 18.0 200:1                                        846  0.12                                                 11.2     __________________________________________________________________________      product is shown by No. of compound

                                      TABLE 19     __________________________________________________________________________     2-(2-substituted ethoxy)-3-isobutyl-5,6-diethylpyrazine                                reaction     BASE                       time      Yield                                              Yield     Example          name             used (g)                                (hr.)                                     product                                          (g) (%)     __________________________________________________________________________      99           ##STR241##      1.76 3.5  556  0.45                                              21.9     100           ##STR242##      2.20 4.0  558  0.77                                              33.9     __________________________________________________________________________      product is shown by No. of compound

                  TABLE 20     ______________________________________     2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline      ##STR243##      ##STR244##                    Product     Reference             amino acidamide          Yield Yield     example HCl used (g) R.sub.1     (g)   (%)     ______________________________________      5      7.63         Pro         4.75  50.0      6      7.63         iso-Pro     4.95  51.6      7      8.32         Bu          7.49  73.0      8      8.32         iso-Bu      6.58  64.0      9      8.32         sec-Bu      6.58  64.0     10      9.04         (CH.sub.2).sub.4 CH.sub.3                                      9.03  82.0     11      9.74         (CH.sub.2).sub.5 CH.sub.3                                      7.81  66.7     12      10.44        (CH.sub.2).sub.6 CH.sub.3                                      9.33  75.0     13      11.14        (CH.sub.2).sub.7 CH.sub.3                                      11.67 89.1     14      11.83        (CH.sub.2).sub.8 CH.sub.3                                      10.50 72.4     15      12.55        (CH.sub.2).sub.9 CH.sub.3                                      12.73 92.2     16      13.95        (CH.sub.2 ).sub.11 CH.sub.3                                      14.00 88.1     17      15.35        (CH.sub.2).sub.13 CH.sub.3                                      16.58 95.8     18      16.75        (CH.sub.2).sub.15 CH.sub.3                                      18.55 99.2     ______________________________________

                                      TABLE 21     __________________________________________________________________________     N-(2-substituted ethyl)-(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yloxy)-a     cetamide     BASE                       reaction                                      Product     Example          name             used (g)                                time (day)                                      No. of comp                                             Yield (g)                                                  Yield (%)     __________________________________________________________________________     104           ##STR245##      1.06 1     368    1.00 66.8     105           ##STR246##      1.24 4     369    1.38 87.0     106           ##STR247##      1.27 2     370    1.07 67.0     107           ##STR248##      1.18 3     371    1.36 87.3     108           ##STR249##      1.25 3     372    1.21 76.0     109           ##STR250##      0.73 2     373    0.73 50.2     __________________________________________________________________________

                                      TABLE 22     __________________________________________________________________________     methyl(3-alkyl-5,6,7,8-tetrahydroquinoxaline-2-yloxy)-acetate     starting compound     N OH            reaction  Product     N R.sub.1    used                     time silica-gel                               No. of                                     Yield                                         Yield     Example          R.sub.1 (g)                     (hr.)                          (g)  compound                                     (g) (%)     __________________________________________________________________________     110  Bu      10.30                     3    210  667   11.54                                         83.2     111  --(CH.sub.2).sub.4 CH.sub.3                  10.10                     3    210  668   11.64                                         79.7     112  --(CH.sub.2).sub.5 CH.sub.3                  11.70                     2.5  210  669   12.24                                         80.0     113  --(CH.sub.2).sub.6 CH.sub.3                  12.40                     2.5  210  670   13.35                                         83.5     114  --(CH.sub.2).sub.7 CH.sub.3                  13.10                     3    200  671   13.02                                         78.0     115  --(CH.sub.2).sub.8 CH.sub.3                  13.80                     3    240  672   13.71                                         78.8     116  --(CH.sub.2).sub.9 CH.sub.3                  14.50                     2.5  210  673   13.61                                         75.2     117  --(CH.sub.2).sub.11 CH.sub.3                  15.90                     3    280  674   16.00                                         82.1     118  --(CH.sub.2).sub.13 CH.sub.3                  17.30                     3    280  675   16.33                                         78.1     119  --(CH.sub.2).sub.15 CH.sub.3                  18.70                     2.5  340  676   18.74                                         84.0     120  Pro     9.60                     3    220  677   10.29                                         78.0     121  sec-Bu  10.30                     2.5  260  678   11.73                                         84.4     __________________________________________________________________________

                                      TABLE 23     __________________________________________________________________________     2-(2-hydroxyethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline                                 reaction     starting compound  methanol                             NaBH.sub.4                                 time silica-gel                                           Product     Example          No. of comp                 used g (mM)                        (ml) (g) (hr.)                                      (g)  No. of comp                                                  Yield (g)                                                       Yield     __________________________________________________________________________                                                       (%)     122  667    12.40(44.6)                        200  10.2                                 2.5  200  685    10.63                                                       95.3     123  668    9.07(31.1)                        200  7.2 3.0  200  686    7.12 86.7     124  669    9.55(31.2)                        200  9.6 2.5  200  687    7.95 91.7     125  670    9.70(30.3)                        200  9.3 3.0  200  688    8.05 91.0     126  671    11.10(33.2)                        300  7.8 3.0  250  689    9.31 91.6     127  672    9.50(27.3)                        250  9.4 3.0  250  690    8.20 93.9     128  673    10.80(29.8)                        250  9.1 2.5  250  691    9.15 92.0     129  674    9.54(24.46)                        250  7.5 3.0  200  692    7.94 89.7     130  675    9.56(22.9)                        250  6.9 3.0  200  693    8.63 96.6     131  676    9.17(32.9)                        250  6.2 3.0  200  694    7.27 84.6     132  677    7.78(29.47)                        200  9.0 3.0  200  695    6.60 95.0     133  678    7.50(27.0)                        200  8.4 2.5  170  696    5.77 85.5     __________________________________________________________________________

                                      TABLE 24     __________________________________________________________________________     2-(2-substituted ethoxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline     starting compound                    chlorin-                       reflux                                                       product     Exam-         No. of     ation                         BASE                      time                                                       No. of                                                           Yield                                                                Yield     ple comp             used g time (hr)                         name              used g  (hr.)                                                       comp                                                           (g)  (%)     __________________________________________________________________________     134 685 1.25 (5 mM)                    3.0                          ##STR251##       0.87 (10 mM)                                                   2.0 517 1.38 86.5     135 685 1.00 (4 mM)                    3.0                          ##STR252##       1.42 (8 mM)                                                   2.0 518 1.23 75.4     136 685 1.00 (4 mM)                    3.0                          ##STR253##       1.69 (8 mM)                                                   2.0 519 0.89 50.3     137 685 1.00 (4 mM)                    3.0                          ##STR254##       1.80 (8 mM)                                                   2.5 520 1.00 54.8     138 686 1.32 (5 mM)                    3.5                          ##STR255##       0.87 (10 mM)                                                   3.0 559 0.92 55.3     139 686 1.32 (5 mM)                    3.5                          ##STR256##       1.42 (10 mM)                                                   2.5 560 1.01 52.1     140 686 1.32 (5 mM)                    3.5                          ##STR257##       1.76 (10 mM)                                                   3.0 561 1.27 60.2     141 686 1.32 (5 mM)                    3.5                          ##STR258##       2.08 (10 mM)                                                   2.5 562 1.24 54.6     142 687 1.39 (5 mM)                    3.5                          ##STR259##       0.87 (10 mM)                                                   3.0 564 0.99 57.1     143 687 1.39 (5 mM)                    3.5                          ##STR260##       1.42 (10 mM)                                                   3.0 565 1.11 55.2     144 687 1.39 (5 mM)                    3.5                          ##STR261##       1.76 (10 mM)                                                   2.5 567 1.25 57.3     145 687 1.39 (5 mM)                    3.5                          ##STR262##       2.10 (10 mM)                                                   2.5 568 1.62 68.9     146 687 1.39 (5 mM)                    3.5                          ##STR263##       2.08 (10 mM)                                                   2.5 569 1.29 55.4     147 688 1.17 (4 mM)                    3.0                          ##STR264##       1.14 (8 mM)                                                   2.5 571 1.01 60.7     148 689 1.53 (5 mM)                    3.0                          ##STR265##       0.87 (10 mM)                                                   2.0 572 1.06 56.5     149 689 1.23 (4 mM)                    3.0                          ##STR266##       1.14 (8 mM)                                                   2.0 573 0.87 50.6     150 689 1.23 (4 mM)                    3.0                          ##STR267##       1.42 (8 mM)                                                   2.0 574 0.95 52.9     151 689 1.23 (4 mM)                    3.0                          ##STR268##       1.68 (8 mM)                                                   2.0 575 0.65 32.6     152 689 1.23 (4 mM)                    3.0                          ##STR269##       1.67 (8 mM)                                                   2.5 576 0.57 28.7     153 690 1.60 (5 mM)                    3.5                          ##STR270##       0.87 (10 mM)                                                   2.0 579 0.63 32.4     154 690 1.28 (4 mM)                    3.5                          ##STR271##       1.14 (8 mM)                                                   2.5 580 0.54 30.4     155 690 1.28 (4 mM)                    3.5                          ##STR272##       1.41 (8 mM)                                                   2.0 581 0.84 43.9     156 690 1.28 (4 mM)                    3.5                          ##STR273##       1.65 (8 mM)                                                   2.0 582 1.01 47.8     157 690 1.28 (4 mM)                    3.5                          ##STR274##       1.80 (8 mM)                                                   2.5 583 0.78 37.0     158 691 1.67 (5 mM)                    3.0                          ##STR275##       0.87 (10 mM)                                                   2.0 585 0.79 39.2     159 691 1.34 (4 mM)                    3.0                          ##STR276##       0.68 (8 mM)                                                   2.5 586 0.65 40.5     160 691 1.34 (4 mM)                    3.0                          ##STR277##       1.14 (8 mM)                                                   2.5 587 0.77 42.0     161 691 1.34 (4 mM)                    3.0                          ##STR278##       1.04 (8 mM)                                                   2.5 588 0.58 32.5     162 691 1.34 (4 mM)                    3.0                          ##STR279##       1.41 (8 mM)                                                   2.5 589 0.93 47.3     163 691 1.34 (4 mM)                    3.0                          ##STR280##       1.68 (8 mM)                                                   2.5 590 1.07 50.8     164 691 1.34 (4 mM)                    3.0                          ##STR281##       2.01 (8 mM)                                                   2.5 591 1.17 51.5     165 691 1.34 (4 mM)                    3.0                          ##STR282##       1.67 (8 mM)                                                   2.0 592 0.70 33.4     166 692 1.09 (3 mM)                    4.5                          ##STR283##       0.53 (6 mM)                                                   3.0 594 0.64 49.5     167 692 1.09 (3 mM)                    5.0                          ##STR284##       0.86 (6 mM)                                                   2.5 595 0.84 57.6     168 692 1.09 (3 mM)                    5.0                          ##STR285##       1.06 (6 mM)                                                   2.5 596 0.92 59.0     169 692 1.09 (3 mM)                    5.0                          ##STR286##       1.24 (6 mM)                                                   2.5 597 0.93 56.4     170 692 1.09 (3 mM)                    4.5                          ##STR287##       1.25 (6 mM)                                                   2.5 598 0.83 50.1     171 693 1.17 (3 mM)                    5.0                          ##STR288##       0.86 (6 mM)                                                   2.5 600 0.74 48.0     172 693 1.17 (3 mM)                    5.0                          ##STR289##       1.06 (6 mM)                                                   2.5 601 0.84 51.1     173 693 1.17 (3 mM)                    5.0                          ##STR290##       1.17 (6 mM)                                                   2.5 602 0.93 54.8     174 693 1.17 (3 mM)                    5.0                          ##STR291##       1.35 (6 mM)                                                   2.5 603 0.92 51.4     175 693 1.17 (3 mM)                    5.0                          ##STR292##       1.51 (6 mM)                                                   2.5 604 0.65 34.7     177 694 1.26 (3 mM)                    4.5                          ##STR293##       0.86 (6 mM)                                                   2.5 607 0.86 52.9     178 694 1.26 (3 mM)                    5.0                          ##STR294##       1.06 (6 mM)                                                   2.0 608 0.88 50.9     179 694 1.26 (3 mM)                    4.5                          ##STR295##       1.32 (6 mM)                                                   2.5 609 0.95 51.1     180 685 1.25 (5 mM)                    6.0                          ##STR296##       1.42 (10 mM)                                                   5.0 817 1.10 59.0     181 689 0.77 (2.5 mM)                    5.5                          ##STR297##       1.60 (12.3 mM)                                                   5.0 830 0.45 43.1     182 685 1.18 (4.7 mM)                    6.5                          ##STR298##       0.85 (10 mM)                                                   5.0 837 0.89 56.3     183 689 0.77 (2.5 mM)                    6.0                          ##STR299##       0.43 (5 mM)                                                   6.0 839 0.61 65.1     184 685 1.25 (5 mM)                    5.0  HNEt.sub.2        1.46 (20 mM)                                                   24  850 0.38 25.0     185 689 0.77 (2.5 mM)                    7.0  HNEt.sub.2        0.73 (10 mM)                                                   24  851 0.47 52.1     __________________________________________________________________________

                                      TABLE 25     __________________________________________________________________________     NMR spectrum, Mass spectrum and Rf-value on silica-gel layer     chromatography     Comp. No.           NMR (CDCl.sub.3, inner standard TMS) ppm                                           MASS Rf     __________________________________________________________________________     034   2.34(3H, s), 2.40(3H, s), 2.46(3H, s), 3.76(3H, s), 4.89(2H,                                           211     035   1.53(3H, d, J=6.9), 2.28(3H, s), 2.34(3H×2, s), 3.65(3H, s),           5.17                            225           (1H, q, J=6.9)     036   2.36(3H, s), 2.41(3H, s), 2.51(3H, s), 3.70(3H, s), 6.11(1H,                                           287           7.3-7.6(5H, m)     037   2.30(3H, s), 2.35(6H, s), 4.83(2H, s)                                           197     038   1.66(2H, d, J=7.1), 2.32(3H, s), 2.38(3H, s), 2.45(3H, s),                                           2117           (1H, q, J=7.1)     039   2.33(3H, s), 2.35(3H, s), 2.38(3H, s), 6.05(1H, s), 7.3-7.6(5H,                                           273     066   2.32(3H, s), 2.35(3H, s), 2.39(3H, s), 2.46(3H, s), 2.3-2.5(4H,                                           279, 179     067   1.5-1.7(3H×2), 2.35(3H, s), 2.39(3H, s), 2.47(3H, s),                                           263, 179           (4H, m), 4.99(2H, s)     068   2.35(3H, s), 2.39(3H, s), 2.46(3H, s), 2.2-2.7(6H, m),                                           309, 179           (4H, m), 4.99(2H, s)     069   2.37(3H, s), 2.41(3H, s), 2.45(3H, s), 3.3-3.6(2H, m), 3.75(2H,                                           240, 179           J≈4.7), 4.84(2H, s), 6.86(1H, bs)     070   2.35(3H×2, s), 2.40(3H× 2, s), 2.47(3H×2, s),           3.6(8H, bs), 5.02               443, 180           (4H, s)                         179     071   2.21(3H×2, s), 2.38(3H, s), 2.42(3H, s), 2.47(3H, s),           3.1-3.5(4H,                     267           m), 4.83(2H, s), 7.0(1H, bs)     072   2.37(3H, s), 2.42(3H, s), 2.48(3H, s), 3.07(2H, t, J≈6.1),           3.54                            332, 179           (2H, t, J≈6.1), 79(2H, s), 6.8(1H, bs), 7.0-7.4(5H, m)     073   2.38(3H, s), 2.42(3H, s), 2.51(3H, s), 2.3-2.6(6H, m), 3.42(2H,                                           309, 240           J≈5.7), 3.5-3.8(4H, m), 4.84(2H, s)                                           179     074   1.3-1.7(6H, m), 2.38(3H, s), 2.42(3H, s), 2.50(3H, s),                                           307, 240           (6H, m), 3.41(2H, sext, J≈5.6), 3.76(1H, t, J≈5.6),           4.84(2H, s)                     179     075   2.36(3H, s), 2.40(3H, s), 2.47(3H, s), 3.4-3.8(8H, m), 4.99(2H,                                           266, 179     076   2.42(3H, s), 2.46(3H, s), 2.50(3H, s), 2.3-2.6(12H, m),                                           3520(2H,           q, J≈6), 3.62(2H, t, J≈5.2), 4.84(2H, s)     103   2.38(3H, s), 2.42(3H, s), 2.51(3H, s), 2.3-2.6(6H, m),                                           308-2.9           (4H, m), 3.41(2H, q, J≈5.5), 4.84(2H, s), 7.0(1H, bs)     105   2.26(3H, s), 2.38(3H, s), 2.43(3H, s), 2.51(3H, s),                                           322, 1134H,           m), 4.84(2H, s), 7.0(1H, bs)     135   2.37(3H, s), 2.43(3H, s), 2.51(3H, s), 2.2-2.6(10H, m), 3.2-                                           434, 432           (2H, m), 3.42(2H, s), 4.83(2H, s), 7.26(4H, s)                                           223, 125     136   2.26(3H, s), 2.38(3H, s), 2.50(3H, s), 2.2-2.6(10H, m),                                           398, 304           (2H, m), 3.48(2H, s), 4.83(2H, s), 7.30(5H, s)                                           189     137   2.38(3H, s), 2.44(3H, s), 2.46(3H, s), 2.3-2.6(10H, m),                                           434, 432           (2H, m), 3.60(2H, s), 4.84(2H, s), 6.9-7.5(4H, m)                                           223, 125     341   1.33(3H, t, J=7.4), 1.74(2H, br. s), 2.35(3H, s), 2.40(3H, s),                                           399-           2.6(4H, m), 2.92(2H, q, J=7.4), 3.2-3.5(2H, m), 3.5-3.7(4H, m), 6.           44(1H, s), 7.0(1H, br. s), 7.2-7.7(5H, m)     342   1.33(3H, t, J=7.4), 1.77(4H, br. s), 2.34(3H, s), 2.40(3H, s),                                           488, 189           2.6(6H, m), 2.91(2H, q, J=7.4), 3.2-3.5(2H, m), 3.49(2H, s), 6.42           (1H, s), 7.0-7.7(11H, m)     343   1.33(3H, t, J=7.4), 1.6(4H, br. s), 2.34(3H, s), 2.40(3H, s),                                           524, 522           2.8(6H, m), 2.92(2H, q, J=7.4), 3.2-3.5(2H, m), 3.43(2H, s),                                           2232           (1H, s), 7.26(1H, s), 7.2-7.6(5H, m)     344   1.34(3H, t, J=7.4), 1.66(4H, br. s), 2.35(3H, s), 2.40(3H, s),                                           533, 234           2.6(6H, m), 2.92(2H, q, J=7.4), 3.2-3.5(2H, m), 2.56(2H, s), 6.43           (1H, s), 7.0(1H, br. s), 7.2-7.7(7H, m), 8.18(2H, d, J=8.8)     345   1.34(3H, t, J=7.4), 1.90(2H, br. s), 2.34(3H, s), 2.41(3H, s),                                           560, 558           2.6(8H, m), 2.92(2H, q, J=7.4), 3.2-3.5(2H, m), 3.55(2H, s),                                           556, 258           (1H, s), 7.0-7.7(9H, m)         256     346   1.34(3H, t, J=7.4), 1.73(2H, br. s), 2.35(3H, s), 2.38(3H, s),                                           474, 330           2.6(6H, m), 2.88(2H, q, J=7.4), 3.0-3.2(2H, m), 3.3-3.5(2H,                                           175           6.45(1H, s), 6.7-7.7(10H, m)     347   1.31(3H, t, J=7.4), 1.6-2.1(4H, m), 2.34(3H, s), 2.40(3H, s),                                           521, 520           2.8(8H, m), 2.90(2H, q, J=7.4), 3.2-3.5(2H, m), 3.54(2H, s),                                           2213           (1H, s), 6.8-7.7(10H, m)     348   1.31(3H, t, J=7.4), 1.6-2.1(2H, m), 2.34(3H, s), 2.40(3H, s),                                           538, 536           2.8(12H, m), 3.1-3.5(2H, m), 3.54(2H, s), 6.43(1H, s),                                           239, 237           s), 7.2-7.6(5H, m)     376   1.23(3H×2, t, J≈7.6), 1.4-2.2(8H, m), 2.2-3.6(10H,           m), 4.21(4H,                    487, 174                                                0.44           s), 4.83(2H, s), 6.51(1H, br. s), 7.0-7.4(10H, m)     377   1.22(3H, t, J≈7.6), 1.26(3H, t, J=7.6), 1.6-2.0(2H, m),           2.2-2.5                         520, 207                                                0.38           (8H, m), 2.69(2H, q, J≈7.6), 2.77(2H, q, J≈7.6),           3.1-3.6(2H, m),           3.36(2H, s), 4.18(2H, s), 4.81(2H, s), 6.4(1H, br. s), 6.8-7.4(9H,           m)     379   1.22(3H, t, J≈7.6), 1.26(3H, t, J=7.6), 1.6-2.0(2H, m),           2.2-3.0                         538, 536                                                0.40           (14H, m), 3.0-3.6(2H, m), 3.36(2H, s), 4.18(2H, s), 4.81(2H,                                           225, 223           6.4(1H, br. s), 7.0-7.4(9H, m)     381   1.23(2H×2, t, J≈7.6), 1.6-1.8(2H, m), 2.2-3.0(14H,           m), 3.0-3.5                     524, 522                                                0.62           (2H, m), 4.19(2H, s), 4.84(2H, s), 6.51(1H, br. s), 6.8-7.4(9H, m)     382   1.22(3H, t, J≈7.6), 1.25(3H×2, t, J≈7.6),           1.4-2.0(2H, m), 2.2-            552, 550                                                0.37           3.0(14H, m), 3.0-3.4(2H, m), 3.50(2H, s), 4.07(2H, s),                                           343, 237           s), 6.4(1H, br. s), 7.0-7.4(9H, m)     491   1.23(3H, t, J≈7.6), 2.32(3H×2), 2.3-3.0(8H, m),           3.6-3.8(4H, m),                 266, 114                                                0.33           4.0-4.3(2H, m)     492   1.23(3H, t, J≈7.4), 1.3-2.0(6H, m), 2.31(3H, s), 2.33(2H,           s), 2.5-                        264, 179                                                0.28           3.0(8H, m), 4.2-4.5(2H, m)     493   0.9-1.2(3H, m), 1.23(3H, t, J≈7.4), 1.3-2.0(5H, m),           2.31(3H, s),                    278, 111                                                0.29           2.33(3H, s), 2.5-3.0(8H, m), 4.2-4.5(2H, m)     494   1.23(3H, t, J≈7.4), 2.30(3H×2, s), 2.31(3H, s),           2.3-3.0(12H, m),                279, 113                                                0.15           4.0-4.3(2H, m)     495   1.22(3H, t, J≈7.4), 2.31(3H×2, s), 2.3-3.0(14H, m),           3.62(2H, t,                     309, 143                                                0.06           J=5.4), 4.0-4.3(2H, m)     496   1.23(3H, t, J≈7.4), 2.31(3H×2, s), 2.3-3.0(14H, m),           3.5-3.8(6H,                     353, 187                                                0.11           m), 4.0-4.3(3H, m)     497   1.22(3H, t, J≈7.4), 2.31(3H×2, s), 2.3-3.0(12H, m),           3.52(2H, s),                    355, 189                                                0.38           4.0-4.3(2H, m), 7.30(5H, s)     498   1.22(3H, t, J≈7.4), 2.31(3H×2, s), 2.3-3.0(12H, m),           3.48(2H, s),                    391, 389                                                0.36           4.0-4.3(2H, m), 7.29(4H, s)     223     499   1.22(3H, t, J≈7.4), 2.31(3H×2, s), 2.3-3.0(12H, m),           3.46(2H, s),                    385, 219                                                0.33           3.79(3H, s), 4.0-4.3(2H, m), 6.84(2H, d, J=8.6), 7.22(2H, d, J=           8.6)     500   1.22(3H, t, J≈7.4), 2.31(3H×2, s), 2.3-3.0(12H, m),           3.47(2H, s),                    373, 207                                                0.35           4.0-4.3(2H, m), 6.8-7.4(4H, m)     501   1.22(3H, t, J≈7.4), 2.31(3H, s), 2.33(3H, s), 2.3-3.0(12H,           m),                             400, 234                                                0.39           3.59(2H, s), 4.0-4.2(2H, m), 7.50(2H, d, J=8.8), 8.17(2H, d, J=           8.8)     502   1.23(3H, t, J≈7.4), 1.6-2.0(2H, m), 2.31(3H, s), 2.33(3H,           s), 2.5-                        414, 248                                                0.28           3.0(12H, m), 3.72(2H, s), 4.0-4.3(2H, m), 7.51(2H, d,           J≈8.8),           8.19(2H, d, J≈8.8)     503   1.23(3H, t, J≈7.4), 1.6-2.0(2H, m), 2.31(3H×2, s),           2.5-3.0(12H,                    387  0.20           m), 3.60(2H, s), 4.0-4.3(2H, m), 6.8-7.4(4H, m)     504   1.22(3H, t, J≈7.4), 1.6-2.0(2H, m), 2.31(3H×2, s),           2.5-3.0(12H,                    405, 403                                                0.23           m), 7.27(4H, s)                 237     511   2.31(3H×2, s), 2.4-2.7(6H, m), 3.6-3.8(4H, m), 4.0-4.3(2H,           s),                             328, 114                                                0.41           7.1-7.5(5H, m)     512   2.30(3H×2, s), 2.3-2.7(10H, m), 3.51(2H, s), 4.0-4.2(2H,                                           417, 202                                                0.37           4.08(2H, s), 7.1-7.5(10H, m)    189     516   1.6-2.0(2H, m), 2.30(3H×2, s), 2.5-3.0(10H, m), 3.58(2H,                                           467, 465                                                0.24           3.9-4.2(2H, m), 4.08(2H, s), 7.1-7.5(10H, m)                                           251, 237     536   2.30(3H, s), 2.34(3H, s), 2.41(3H, s), 2.4-2.7(6H, m),                                           252, 101                                                0.30           (4H, m), 4.0-4.3(2H, m)     537   1.2-1.8(6H, m), 2.30(3H, s), 2.36(3H, s), 2.41(3H, s),                                           250, 111                                                0.20           (6H, m), 4.1-4.3(2H, m)     538   2.29(3H, s), 2.32(3H, s), 2.40(3H, s), 2.3-2.8(10H, m),                                           341, 189                                                0.27           s), 4.0-4.3(2H, m), 7.30(5H, s)     539   2.30(3H, s), 2.32(3H, s), 2.41(3H, s), 2.3-2.8(10H, m),                                           377, 375                                                0.27           s), 4.0-4.3(2H, m), 7.26(4H, s) 223     540   2.30(3H, s), 2.33(3H, s), 2.41(3H, s), 2.4-2.8(10H, m),                                           359, 220                                                0.20           s), 4.0-4.3(2H, m), 6.8-7.4(4H, m)                                           207     541   1.6-2.0(2H, m), 2.30(3H, s), 2.32(3H, s), 2.41(3H, s),                                           391, 389                                                0.17           (10H, m), 3.60(2H, s), 4.0-4.3(2H, m), 7.26(4H, s)                                           237, 165     544   1.20(3H×2, d, J=6.8), 2.32(3H×2, s), 2.4-2.8(6H, m),           3.42(1H,                        280, 114                                                0.33           sept, J=6.8), 3.5-3.8(4H, m), 4.0-4.3(2H, m)     546   1.20(3H×2, d, J=6.8), 2.30(3H×2, s), 2.2-2.8(10H, m),           3.42(1H,                        405, 403                                                0.33           sept, J=6.8), 3.47(2H, s), 3.9-4.2(2H, m), 7.27(4H, s)     547   1.20(3H×2, d, J=6.8), 1.6-2.0(2H, m), 2.30(3H×2, s),           2.5-3.0                         419, 417                                                0.23           (10H, m), 3.42(1H, sept, J=6.8), 3.60(2H, s), 3.9-4.2(2H,                                           237           7.27(4H, s)     550   1.0-1.3(12H, m), 1.3-1.8(6H, m), 2.3-2.8(10H, m), 3.42(1H,                                           306, 112                                                0.30           J=6.8), 4.0-4.3(2H, m)     551   0.91(3H, t, J≈6), 1.20(3H×2, d, J=6.8),           1.21(3H×2, d, J=7.6),     363, 155                                                0.25           1.2-1.6(4H, m), 2.3-2.8(16H, m), 3.42(1H, sept, J=6.8), 4.0-4.2(2H,           m)     552   1.20(3H×2, d, J=6.8), 1.21(3H×2, d, J=7.6),           2.3-2.8(14H, m),                397, 189                                                0.35           3.42(1H, sept, J=6.8), 3.51(2H, s), 4.0-4.2(2H, m), 7.30(5H, s)     553   1.20(3H×2, d, J=6.8), 1.21(3H×2, d, J=7.6), 1.6-2.0(2H,           m), 2.4-                        441, 233                                                0.21           3.0(14H, m), 3.42(1H, sept, J=6.8), 3.59(2H, s), 3.80(3H, s), 3.9-           4.2(2H, m), 6.84(2H, d, J=8.8), 7.24(2H, d, J=8.8)     556   0.94(3H×2, d, J=6.7), 1.20(3H, t, J=7.6), 1.21(3H, t, J=7.6),           2.0-                            411, 189                                                0.32           2.4(1H, m), 2.4-3.0(16H, m), 3.53(2H, s), 4.0-4.3(2H, m), 7.30           (5H, s)     558   0.94(3H×2, d, J=6.7), 1.20(3H, t, J=7.6), 1.21(3H, t,                                           455, 246                                                0.17           1.6-2.0(2H, m), 2.0-2.4(1H, m), 2.4-3.0(16H, m), 3.60(2H, s),                                           1210           (3H, s), 3.9-4.2(2H, m), 6.84(2H, d, J=8.6), 7.25(2H, d, J=8.6)     648   2.32(3H, s), 2.35(3H×2, s), 3.3-3.5(2H, m), 4.2-4.4(2H, m),           4.99                            304, 302           (2H, s), 8.0(1H, br. s)         222, 179     649   2.38(3H, s), 2.43(3H, s), 2.48(3H, s), 3.6-3.8(4H, m),                                           260, 258           s), 6.8(1H, br. s)     650   0.7-2.0(10H, m), 2.1-2.5(1H, m), 2.37(3H, s), 2.42(3H, s),                                           3218           (3H, s), 2.81(2H, t, J=5.8), 3.2-3.5(3H, m), 4.84(2H, s), 7.1           (1H, br. s)     651   1.29(3H, t, J≈7), 2.36(3H, s), 2.41(3H, s), 2.87(2H, q,           J≈7), 3.69              301, 121           (3H, s), 6.14(1H, s), 7.3-7.7(5H, m)     652   1.22(3H, t, J≈7.6), 2.31(3H, s), 2.37(3H, s), 2.83(2H, q,           J≈7.6),                 287           5.65(1H, br. s), 6.14(1H, s), 7.2-7.6(5H, m)     653   1.22(3H/2, t, J≈7.4), 1.27(3H/2, t, J≈7.4),           2.72(1H, q, J=7.4),             364, 362           2.80(1H, q, J≈7.4), 3.2-3.5(4H, m), 4.17(2H, s), 4.81(2H,           s), 6.9                         241, 146           (1H, br. s), 7.0-7.4(5H, m)     654   1.19(3H, t, J=5.7), 1.23(3H, t, J=5.7), 2.65(2H, q, J=5.7),                                           3153           (2H, q, J=5.7), 3.73(3H, s), 4.16(2H, s), 4.85(2H, s), 7.0-7.5(5H,           m)     655   1.19(3H, t, J=7.6), 1.21(3H, t, J=7.6), 2.65(2H, q, J=7.6),                                           3015           (2H, q, J=7.6), 4.16(2H, s), 4.88(2H, s), 6.98(1H, br. s), 7.0-7.4           (5H, m)     656   1.22(3H, t, J=7.4), 1.27(3H, t, J=7.4), 2.72(2H, q, J=7.4),                                           364, 362           (2H, q, J=7.4), 3.2-3.5(4H, m), 4.17(2H, s), 4.81(2H, s),                                           241, 146           br. s), 7.0-7.4(5H, m)     657   1.23(3H, t, J≈7.6), 1.26(3H, t, J≈7.6), 1.6.1.8(2H,           m), 2.34                        413, 102                                                0.50           (2H×2, J≈4.7), 2.70(2H, q, J≈7.6), 2.78(2H,           q, J≈7.6), 3.0-3.4           (2H, m), 3.4-3.6(4H, m), 4.18(2H, s), 4.83(2H, s), 6.31(1H, br. s),           7.0-7.4(5H, m)     658   1.23(3H, t, J=7.6), 1.4-2.0(2H, m), 2.2-3.6(10H, m), 4.21(2H,                                           487, 174                                                0.44           4.83(2H, s), 6.51(1H, br. s), 70.-7.4(10H, m)     662   1.23(3H, t, J≈7.6), 2.39(3H×2, s), 2.83(2H, q,           J≈7.4), 3.75(3H, s)     225           4.88(2H, s)     663   2.33(3H, s), 2.41(3H, s), 3.73(3H, s), 4.15(2H, s), 4.87(2H,                                           287           7.0-7.4(5H, m)     664   1.27(3H×2, d, J=6.8), 2.32(3H, s), 2.40(3H, s), 3.34(1H,           sept, J=                        239           6.8), 3.75(3H, s), 4.90(2H, s)     665   1.23(3H, t, J=7.6), 1.24(3H, t, J=7.6), 1.28(3H×2, d,                                           267.8),                                                0.89           2.65(2H, q, J=7.6), 2.73(2H, q, J=7.6), 3.34(1H, sept, J=6.8),           3.74(3H, s), 4.87(2H, s)     666   0.94(3H×2, d, J=6.7), 1.20(3H, t, J≈7.3), 1.21(3H, t,           J≈7.3), 2.18            281  0.68           (1H, sept, J=7.3), 2.5-2.9(6H, m), 3.74(3H, s), 4.86(2H, s)     679   2.38(3H, s), 2.41(3H×2, s), 3.64(1H, t, J≈5.5),           3.8-4.1(3H, m),                 183  0.59           4.4-4.6(2H, m)     680   1.23(3H, t, J≈7.4), 2.32(3H×2, s), 2.78(2H, q,           J≈7.4), 3.8-4.1         197  0.64           (3H, m), 4.4-4.6(2H, m)     681   2.38(3H, s), 2.45(3H, s), 2.6-2.8(1H, br. m), 3.7-3.9(2H, m),                                           2591 0.91           (2H, s), 4.3-4.5(2H, m), 7.1-7.4(5H, m)     682   1.24(3H×2, d, J≈6.8), 2.37(3H, s), 2.42(3H, s),           3.29(1H, sept, J≈       211  0.57           6.8), 3.6-4.0(2H, m), 4.3-4.5(2H, m)     683   1.1-1.4(12H, m), 2.70(2H, q, J=7.6), 3.30(1H, sept, J=6.8),                                           239- 0.63           4.1(3H, m), 4.4-4.6(2H, m)     684   0.93(3H×2, d, J≈6.7), 1.20(3H, t, J≈7.3),           1.26(3H, t, J≈7.3),     253  0.71           2.13(1H, sept, J≈7.3), 2.6-2.9(6H, m), 3.67(1H, t,           J≈5.3), 3.8-           4.1(3H, m), 4.4-4.6(2H, m)     697   0.91(3H, t, J≈6), 1.20(3H×2, d, J=6.8), 1.2-1.6(4H,           m), 2.2-2.8                     345  0.18           (12H, m), 2.31(3H×2, q), 3.43(1H, sept, J=6.8), 4.0-4.3(2H,           m)     810   0.91(3H, t), 1.1-1.6(4H, m), 2.30(3H, s), 2.34(3H, s),                                           3071(3H,                                                0.26           s), 4.15(2H, t), 2.3-2.7(12H, m)     812   0.91(3H, t), 1.23(3H, t), 1.1-1.6(4H, m), 2.31(6H, s),                                           321-2.9                                                0.19           (14H, m), 4.14(2H, t)     814   0.91(3H, t), 1.20(6H, t), 1.1-1.7(4H, m), 2.31(6H, s),                                           335-2.9                                                0.22           (12H, m), 3.42(1H, sept), 4.14(2H, t)     822   2.30(3H, s), 2.33(3H, s), 2.41(3H, s), 2.3-2.7(12H, m),                                           2952(2H,                                                0.02           t), 4.15(3H, t)     825   1.20(6H, d), 2.31(6H, s), 2.1-2.9(12H, m), 3.42(1H, sept),                                           3232 0.06           (2H, t), 4.14(2H, t)     826   1.21(6H, d), 1.21(6H, t), 2.0-2.9(12H, m), 3.42(1H, sept),                                           3512 0.04           (2H, t), 4.13(2H, t)     834   1.20(6H, d), 1.3-1.8(6H, m), 2.31(3H, s), 2.34(3H, s),                                           278-2.7                                                0.22           (6H, m), 3.42(1H, sept), 4.21(2H, t)     842   1.04(6H, t), 2.30(3H, s), 2.35(3H, s), 2.41(3H, s),                                           238-2.8(6H,                                                0.63           m), 4.11(2H, t)     844   1.04(6H, t), 1.23(3H, t), 2.31(3H, s), 2.34(3H, s),                                           252-2.9(8H,                                                0.46           m), 4.11(2H, t)     846   1.09(6H, t), 1.20(6H, d), 2.31(3H, s), 2.34(3H, s),                                           266-2.9(6H,                                                0.63           m), 3.43(1H, sept), 4.14(2H, t)     848   0.99-1.27(18H, m), 2.4-2.9(10H, m), 3.44(1H, sept), 4.13(2H,                                           294  0.27     __________________________________________________________________________

                                      TABLE 26     __________________________________________________________________________     physical properties of 2-hydroxy-3-substituted-5,6,7,8-tetrahydroquinoxaki     ne      ##STR300##     R.sub.1 NMR (CDCl.sub.3  , inner standard TMS) δ ppm                                               MASS     __________________________________________________________________________     Me      1.78-1.84 (4H, m), 2.42 (3H, s), 2.66 (4H, m), 13.05 (1H, br,                                               165     Et      1.25 (3H, t), 1.7-1.9 (4H, m), 2.5-2.8 (4H, m), 2.80 (2H, q),             13.06 (1H,                        179             br, s)     Pro     1.00 (4H, t), 1.55 (6H, m), 2.67-2.83 (6H, m), 13.09 (1H, br,                                               193     iso-Pro 1.24 (3H×2, d×2, J=6.8), 1.7-2.0 (4H, m), 2.5-2.8             (4H, m), 3.41 (1H,                193             sept, J=6.8), 12.9 (1H, br, s)     Bu      0.94 (3H, t), 1.24-2.00 (8H, m), 2.55-2.85 (6H, m), 12.99 (1H,             br, s)                            207     iso-Bu  0.96 (3H×2, d), 1.6-2.0 (4H, m), 2.0-2.4 (1H, m), 2.5-2.8             (6H, m)                           207     sec-Bu  0.96 (3H×2, d×2, J=6.7), 1.6-2.2 (5H, m), 2.5-2.8             (6H, m)                           207     (CH.sub.2).sub.4 CH.sub.3             0.90 (3H, t, J=6.3), 1.2-1.5 (4H, m), 1.5-1.9 (6H, m), 2.5-2.9             (6H, m)                           221, 164     (CH.sub.2).sub.5 CH.sub.3             0.88 (3H, t, J=7.9), 1.1-1.5 (6H, m), 1.5-2.0 (6H, m), 2.4-2.9             (6H, m)                           235     (CH.sub.2).sub.6 CH.sub.3             0.88 (3H, t, J≈7.4), 1.1-1.5 (8H, m), 1.5-2.0 (6H, m),             2.5-2.9 (6H, m)                   249, 164     (CH.sub.2).sub.7 CH.sub.3             0.88 (3H, t, J=7.5), 1.1-1.5 (10H, m), 1.5-2.0 (6H, m), 2.5-2.9             (6H, m)                           263     (CH.sub.2).sub.8 CH.sub.3             0.88 (3H, t, J=6.2), 1.1-1.5 (12H, m), 1.5-2.0 (6H, m), 2.5-2.8             (6H, m)                           277, 164     (CH.sub.2).sub.9 CH.sub.3             0.88 (3H, t, J≈6), 1.2-2.0 (20H, m), 2.5-2.9 (6H, m),             12.7(1H, br, s)                   291     (CH.sub.2).sub.11 CH.sub.3             0.88 (3H, t, J≈6), 1.1-1.9 (24H, m), 2.4-2.8 (6H,                                               319, 164     (CH.sub.2).sub.13 CH.sub.3             0.88 (3H, t, J≈6), 1.1-1.9 (28H, m), 2.5-2.8 (6H,                                               347, 164     (CH.sub.2).sub.15 CH.sub.3             0.88 (3H, t, J≈6), 1.1-1.9 (32H, m), 2.5-2.8 (6H,                                               375, 164     CH.sub.2 Ph             1.6-2.0 (4H, m), 2.4-2.7 (4H, m), 4.02 (2H, s), 7.0-7.4 (4H,                                               241     CH.sub.2 CH.sub.2 Ph             1.6-2.0 (4H, m), 2.5-2.8 (4H, m), 3.06 (2H×2, s), 7.1-7.3             (5H, s), 12.9                     255             (1H, br, s)     __________________________________________________________________________

                                      TABLE 27     __________________________________________________________________________     physical properties of a compound of the present invention     Comp. No.           NMR (CDCl.sub.3, inner standard TMS) δ ppm                                            MASS Rf     __________________________________________________________________________     368   1.7-2.0 (4H, m), 2.2-3.0 (14H, m), 3.0-3.6 (2H, m), 3.40 (2H, s),           4.17                             500, 189                                                 0.45           (2H, s), 4.79 (2H, s), 6.4 (1H, br, s), 7.0-7.4 (10H, m)     369   1.6-2.0 (4H, m), 2.1-3.0 (14H, m), 3.0-3.6 (2H, m), 3.34 (2H, s),           3.79                             530, 219                                                 0.43           (3H, s), 4.17 (2H, s), 4.79 (2H, s), 6.4 (1H, br, s), 6.7-7.4 (9H,           m)     370   1.6-2.0 (4H, m), 2.1-3.0 (14H, m), 3.0-3.6 (2H, m), 3.35 (2H, s),           4.18                             535, 533                                                 0.4           (2H, s), 4.79 (2H, s), 6.3 (1H, br, s), 7.0-7.4 (9H,                                            223     371   1.6-2.0 (4H, m), 2.3-3.0 (10H, m), 3.0-3.4 (6H, m), 4.19 (2H, s),           4.82                             522, 520                                                 0.48           (2H, s), 6.4 (1H, br, s), 6.7-7.4 (9H, m)                                            209     372   1.5-2.1 (6H, m), 2.3-3.0 (14H, m), 3.0-3.4 (2H, m), 3.51 (2H, s),           4.17                             532, 221                                                 0.38           (2H, s), 4.79 (2H, s), 6.3 (1H, br, s), 6.9-7.4 (9H, m)     373   1.6-2.1 (2H, m), 2.2-3.0 (10H, m), 3.0-3.4 (4H, m), 4.15 (2H, s),           4.81                             486, 342                                                 0.49           (2H, s), 6.3 (1H, br, s), 6.6-7.4 (10H, m)                                            175     517   0.93 (3H, t, J≈6.6), 1.2-2.0 (8H, m), 2.4-3.0 (12H, m),           3.6-3.8 (4H,                     320, 102                                                 0.42           m), 3.9-4.2 (2H, m)     518   0.93 (3H, t, J≈6.6), 1.2-2.0 (8H, m), 2.4-3.0 (16H, m),           3.53 (2H, s),                    409, 189                                                 0.41           3.9-4.2 (2H, m), 7.30 (5H, s)     519   0.93 (3H, t, J≈6.6), 1.2-2.0 (8H, m), 2.4-3.0 (16H, m),           3.47 (2H, s),                    445, 443                                                 0.43           3.9-4.2 (2H, m), 7.27 (4H, s)    227     520   0.93 (3H, t, J≈6.6), 1.2-2.0 (10H, m), 2.4-3.0 (16H, m),           3.60 (2H, s),                    459, 457                                                 0.29           3.9-4.2 (2H, m), 7.27 (4H, s)    237     521   0.93 (3H, t, J≈6.6), 1.2-2.0 (8H, m), 2.4-3.0 (12H, m),           3.0-3.3 (4H,                     395, 175                                                 0.61           m), 4.0-4.3 (2H, m), 6.7-7.4 (5H, m)     522   0.93 (3H, t, J≈6.6), 1.2-2.0 (8H, m), 2.5-3.0 (12H, m),           3.2-3.2 (4H,                     425, 205                                                 0.69           m), 3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m)     559   0.89 (3H, t, J≈6), 1.2-2.0 (10H, m), 2.4-2.9 (12H, m),           3.6-3.8 (4H,                     334, 102                                                 0.44           m), 3.9-4.2 (2H, m)     560   0.89 (3H, t, J≈6), 0.91 (3H, t, J≈6), 1.2-2.0 (14H,           m), 2.2-2.9 (18H,                389, 155                                                 0.24           m), 3.9-4.2 (2H, m)     561   0.89 (3H, t, J≈6), 1.1-2.0 (10H, m), 2.4-2.9 (16H, m), 3.53           (2H, s),                         423, 189                                                 0.31           3.9-4.2 (2H, m), 7.30 (5H, s)     562   0.89 (3H, t, J≈6), 1.1-2.0 (12H, m), 2.4-2.9 (16H, m), 3.61           (2H, s),                         455, 234                                                 0.19           3.9-4.2 (2H, m), 6.8-8.4 (4H, m) 221     563   0.89 (3H, t, J≈6), 1.2-2.0 (10H, m), 2.5-2.9 (12H, m),           3.0-3.2 (4H,           m), 3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m)     564   0.87 (3H, t, J≈6), 1.1-2.0 (12H, m), 2.4-2.9 (12H, m),           3.6-3.8 (4H,                     348, 101                                                 0.32           m), 3.9-4.2 (2H, m)     565   0.87 (3H, t, J≈6), 0.91 (3H, t, J≈6), 1.1-2.0 (16H,           m), 2.1-2.9 (18H,                403, 155                                                 0.20           m), 3.9-4.2 (2H, m)     567   0.87 (3H, t, J≈6), 1.1-2.0 (12H, m), 2.3-2.9 (16H, m), 3.52           (2H, s),                         437, 189                                                 0.28           2.9-4.2 (2H, m), 7.30 (5H, s)     568   0.87 (3H, t, J≈6), 1.1-2.0 (12H, m), 2.4-2.9 (16H, m), 3.52           (2H, s),                         473, 471                                                 0.31           3.9-4.2 (2H, m), 7.30 (4H, s)    236, 223     569   0.87 (3H, t, J≈6), 1.1-2.0 (14H, m), 2.4-3.0 (16H, m), 3.60           (2H, s),                         469, 234                                                 0.20           3.9-4.2 (2H, m), 6.8-7.4 (4H, m) 221     570   0.87 (3H, t, J≈6), 1.1-2.0 (12H, m), 2.5-3.0 (12H, m),           2.9-3.2 (4H,                     453, 218                                                 0.53           3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m)                                            205     571   0.7-1.0 (6H, m), 1.1-2.0 (18H, m), 2.2-2.9 (18H, m), 3.9-4.2 (2H,           m)                               417, 155                                                 0.33     572   0.87 (3H, t, J≈6), 1.1-2.0 (16H, m), 2.4-2.9 (12H, m),           3.6-3.8 (4H,                     376  0.58           m), 3.9-4.2 (2H, m)     573   0.7-1.0 (6H, m), 1.1-2.0 (20H, m), 2.2-2.9 (18H, m), 3.9-4.2 (2H,           m)                               431, 155                                                 0.27     574   0.87 (3H, t, J≈6), 1.1-2.0 (16H, m), 2.4-2.9 (16H, m), 3.53           (2H, s),                         465, 189                                                 0.52           3.9-4.2 (2H, m), 7.30 (5H, s)     575   0.87 (3H, t, J≈6), 1.1-2.0 (16H, m), 2.3-2.9 (16H, m),           3.9-4.2 (2H,                     501, 499                                                 0.43           m), 7.26 (4H, s)                 223     576   0.87 (3H, t, J≈6), 1.1-2.0 (18H, m), 2.5-2.9 (16H, m), 3.59           (2H, s),                         497, 235                                                 0.24           3.9-4.2 (2H, m), 6.8-7.4 (4H, m) 221     577   0.88 (3H, t, J≈6), 1.1-2.0 (16H, m), 2.5-2.9 (12H, m),           3.0-3.3 (4H,                     450, 189                                                 0.67           m), 4.0-4.3 (2H, m), 6.7-7.4 (5H, m)                                            175     578   0.87 (3H, t, J≈6), 1.1-2.0 (16H, m), 2.5-2.9 (12H, m),           3.0-3.2 (4H,                     480, 218                                                 0.55           m), 3.77 (3H, s), 4.0-4.2 (2H, m), 6.86 (4H, s)                                            205     579   0.87 (3H, t, J≈6), 1.0-2.0 (18H, m), 2.4-2.9 (12H, m),           3.5-3.8 (4H,                     390, 102                                                 0.39           m), 3.9-4.2 (2H, m)     580   0.87 (3H, t, J≈6), 0.91 (3H, t, J≈6), 1.0-2.0 (22H,           m), 2.3-2.9 (18H,                445, 155                                                 0.29           m), 3.9-4.2 (2H, m)     581   0.87 (3H, t, J≈6), 1.0-2.0 (18H, m), 2.4-2.9 (16H, m), 3.52           (2H, s),                         479, 202                                                 0.32           3.9-4.2 (2H, m)                  189     582   0.87 (3H, t, J≈6), 1.0-2.0 (18H, m), 2.3-2.9 (16H, m), 3.47           (2H, s),                         509, 232                                                 0.28           3.80 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J=8.8), 7.23 (2H, d,           J=8.8)                           219     583   0.87 (3H, t, J≈6), 1.0-2.0 (20H, m), 2.4-3.0 (16H, m), 3.59           (2H, s),                         529, 527                                                 0.39           3.9-4.2 (2H, m), 7.26 (4H, s)    250, 237     584   0.87 (3H t, J≈6), 1.0-2.0 (18H, m), 2.4-2.9 (12H, m),           3.0-3.2 (4H,                     501, 499                                                 0.46           m), 3.9-4.2 (2H, m), 6.7-7.3 (4H, m)                                            222, 209     585   0.87 (3H, t, J≈6), 1.0-2.0 (20H, m), 2.4-2.9 (12H, m),           3.5-3.8 (4H,                     404, 113                                                 0.37           m), 3.9-4.2 (2H, m)              102     586   0.87 (3H, t, J≈6), 1.0-2.0 (26H, m), 2.4-2.9 (12H, m),           4.0-4.3 (4H,                     402, 112                                                 0.29           m)     587   0.87 (3H, t, J≈6), 0.91 (3H, t, J≈6), 1.0-2.0 (24H,           m), 2.2-2.9 (18H,                459, 155                                                 0.26           m), 3.9-4.2 (2H, m)              125     588   0.87 (3H, t, J≈6), 1.0-2.0 (20H, m), 2.3-2.9 (18H, m), 3.62           (2H, t,                          447, 156                                                 0.12           J≈6), 3.9-4.2 (2H, m)    143, 125     589   0.87 (3H, t, J≈6), 1.0-2.0 (20H, m), 2.4-2.9 (16H, m), 3.52           (2H, s),                         493, 202                                                 0.37           3.9-4.2 (2H, m), 7.30 (5H, s)    189     590   0.87 (3H, t, J≈6), 1.0-2.0 (20H, m), 2.3-2.9 (16H, m), 3.52           (2H, s),                         529, 527                                                 0.41           3.9-4.2 (2H, m), 7.26 (4H, s)    236, 223                                            125     591   0.87 (3H, t, J≈6), 1.0-2.0 (20H, m), 2.3-2.9 (16H, m),           3.8-4.2 (2H,                     569, 278                                                 0.66           m), 4.22 (1H, s), 7.0-7.6 (10H, m)                                            167     592   0.87 (3H, t, J≈6), 1.0-2.0 (22H, m), 2.4-3.0 (16H, m), 3.60           (2H, s),                         525, 234                                                 0.27           3.9-4.2 (2H, m), 6.8-7.4 (4H, m) 221     593   0.87 (3H, t, J≈6), 1.0-2.0 (20H, m), 2.4-2.9 (12H, m),           2.9-3.2 (4H,                     509, 218                                                 0.60           m), 3.77 (4H, s), 3.9-4.2 (2H, m), 6.6-7.0 (4H, m)                                            205     594   0.88 (3H, t, J≈6), 1.0-2.0 (24H, m), 2.4-3.0 (12H, m),           3.6-3.8 (4H,                     432, 101                                                 0.34           m), 3.9-4.2 (2H, m)     595   0.88 (3H, t, J≈6), 0.91 (3H, t, J≈6), 1.0-2.0 (28H,           m), 2.2-3.0 (18H,                487, 155                                                 0.16           m), 3.9-4.2 (2H, m)     596   0.88 (3H, t, J≈6), 1.0-2.0 (24H, m), 2.3-2.9 (16H, m), 3.53           (2H, s),                         521, 202                                                 0.21           3.9-4.2 (2H, m), 7.30 (5H, s)    179     597   0.88 (3H, t, J≈6), 1.0-2.0 (24H, m), 2.4-2.9 (16H, m), 3.47           (2H, s),                         551, 232                                                 0.21           3.79 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J≈8.6), 7.22           (2H, d, J=8.6)                   219     598   0.88 (3H, t, J≈6), 1.0-2.0 (26H, m), 2.4-3.0 (16H, m),           3.9-4.2 (2H,                     553, 234                                                 0.15           m), 6.8-7.4 (4H, m)              221     599   0.88 (3H, t, J≈6), 1.0-2.0 (24H, m), 2.5-2.9 (12H, m),           2.9-3.2 (4H,                     537, 208                                                 0.43           m), 3.86 (3H, s), 3.9-4.1 (2H, m), 6.7-7.1 (2H, m)                                            205     600   0.88 (3H, t, J≈6), 0.91 (3H, t, J≈6), 1.0-2.0 (32H,           m), 2.2-2.9 (18H,                515, 155                                                 0.22           m), 3.9-4.2 (2H, m)     601   0.88 (3H, t, J≈ 6), 1.0-2.0 (28H, m), 2.4-2.9 (16H, m),           3.51 (2H, s),                    549, 202                                                 0.36           3.9-4.2 (2H, m), 7.29 (5H, s)    189     602   0.88 (3H, t, J≈6), 1.0-2.0 (28H, m), 2.3-2.9 (16H, m), 3.47           (2H, s),                         567, 549                                                 0.37           3.9-4.2 (2H, m), 6.8-7.4 (4H, m) 220, 207     603   0.88 (3H, t, J≈6), 1.0-2.0 (30H, m), 2.4-3.0 (16H, m), 3.60           (2H, s),                         599, 597                                                 0.30           3.9-4.2 (2H, m), 7.27 (4H, s)    250     604   0.88 (3H, t, J≈6), 1.0-2.0 (28H, m), 2.3-2.9 (16H, m),           3.9-4.2 (2H,                     625, 228                                                 0.71           m), 4.23 (1H, s), 7.0-7.5 (10H, m)                                            167     605   0.88 (3H, t, J≈6), 1.0-2.0 (28H, m), 2.5-3.0 (12H, m),           2.9-3.2 (4H,                     571, 569                                                 0.71           m), 4.0-4.3 (2H, m), 6.8-7.4 (4H, m)                                            222, 209     606   0.88 (3H, t, J≈6), 1.0-2.0 (28H, m), 2.4-2.9 (12H, m),           3.5-3.8 (4H,                     488, 113                                                 0.47           m), 3.9-4.2 (2H, m)     607   0.88 (3H, t, J≈6), 0.91 (3H, t, J≈6), 1.0-2.0 (36H,           m), 2.1-2.8 (18H,                543, 168                                                 0.26           m), 3.9-4.2 (2H, m)              155     608   0.88 (3H, t, J≈6), 1.0-2.0 (32H, m), 2.3-2.9 (16H, m), 3.51           (2H, s),                         578, 202                                                 0.35           3.9-4.2 (2H, m), 7.29 (5H, s)     609   0.88 (3H, t, J≈6), 1.0-2.0 (34H, m), 2.5-2.9 (16H, m), 3.62           (2H, s),                         621, 246                                                 0.25           3.80 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J=8.6), 7.26 (2H, d,           J=8.6)                           121     610   0.88 (3H, t, J≈6), 1.0-2.0 (32H, m), 2.4-2.9 (12H, m),           2.9-3.2 (4H,                     592, 218                                                 0.45           m), 3.76 (3H, s), 3.9-4.2 (2H, m), 6.6-7.0 (4H, m)     659   1.7-1.9 (4H, m), 2.6-2.9 (4H, m), 3.73 (3H, s), 4.16 (2H, s), 4.86           (2H,                             313           s), 7.0-7.4 (5H, m)     660   1.7-1.9 (4H, m), 2.6-3.0 (4H, m), 4.16 (2H, s), 4.87 (2H, s),           7.0-7.5                          299           (5H, m)     661   1.7-1.9 (4H, m), 2.6-2.9 (4H, m), 3.2-3.5 (4H, m), 4.17 (2H, s),           4.85                             362, 360           (2H, s), 7.0-7.5 (5H, m)     667   0.94 (3H, t, J≈7.4), 1.2-2.0 (8H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         279  0.89           4.88 (2H, s)     668   0.89 (3H, t, J≈6), 1.2-2.0 (10H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         293  0.90           4.89 (2H, s)     669   0.88 (3H, t, J≈6), 1.2-2.0 (12H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         307  0.92           4.88 (2H, s)     670   0.88 (3H, t, J≈6), 1.2-2.0 (14H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         321  0.93           4.89 (2H, s)     671   0.87 (3H, t, J≈6), 1.2-2.0 (16H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         335  0.93           4.88 (2H, s)     672   0.87 (3H, t, J≈6), 1.1-2.0 (18H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         349  0.93           4.88 (2H, s)     673   0.87 (3H, t, J≈6), 1.1-2.0 (20H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         363  0.94           4.88 (2H, s)     674   0.87 (3H, t, J≈6), 1.1-2.0 (24H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         391  0.94           4.88 (2H, s)     675   0.88 (3H, t, J≈6), 1.0-2.0 (28H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         419  0.94           4.88 (2H, s)     676   0.88 (3H, t, J≈6), 1.0-2.0 (32H, m), 2.6-3.0 (6H, m), 3.75           (3H, s),                         447  0.95           4.88 (2H, s)     677   0.99 (3H, t, J=7.3), 1.5-2.0 (6H, m), 3.75 (3H, s), 3.89 (2H,                                            265  0.86     678   0.86 (3H, t, J=7.4), 1.25 (2H, d, J=7.8), 1.6-2.0 (6H, m),                                            2.792.9                                                 0.88           (4H, m), 2.9-3.3 (1H, m), 3.74 (3H, s), 4.88 (2H, s)     685   0.93 (3H, t, J≈6.7), 1.1-2.0 (8H, m), 2.6-3.0 (6H, m),           3.6-4.1 (3H,                     251  0.66           m), 4.4-4.6 (2H, m)     686   0.89 (3H, t, J≈6), 1.2-2.0 (10H, m), 2.6-3.0 (6H, m), 3.7           (1H, br, s),                     265  0.67           3.8-4.1 (2H, m), 4.4-4.6 (2H, m)     687   0.88 (3H, t, J≈6), 1.0-2.0 (12H, m), 2.6-3.0 (6H, m), 3.7           (1H, br, s),                     279  0.67           3.8-4.1 (2H, m), 4.3-4.6 (2H, m)     688   0.88 (3H, t, J≈6), 1.2-2.0 (14H, m), 2.6-3.0 (6H, m), 3.7           (1H, br, s),                     293  0.67           3.8-4.1 (2H, m), 4.4-4.6 (2H, m)     689   0.88 (3H, t, J≈6), 1.1-2.0 (16H, m), 2.6-3.0 (6H, m), 3.7           (1H, br, s),                     307  0.69           3.8-4.1 (2H, m), 4.4-4.6 (2H, m)     690   0.87 (3H, t, J≈6), 1.0-2.0 (18H, m), 2.6-3.0 (6H, m), 3.7           (1H, br, s),                     321  0.70           3.8-4.1 (2H, m), 4.4-4.6 (2H, m)     691   0.88 (3H, t, J≈6), 1.1-2.0 (20H, m), 2.6-3.0 (6H, m),           3.7-4.1 (3H, m),                 335  0.72           4.4-4.6 (2H, m)     692   0.88 (3H, t, J≈6), 1.0-2.0 (24H, m), 2.6-3.0 (6H, m),           3.7-4.1 (3H, m),                 363  0.78           4.4-4.6 (2H, m)     693   0.88 (3H, t, J≈6), 1.0-2.0 (28H, m), 2.5-3.0 (6H, m),           3.7-4.1 (3H, m),                 391  0.81           4.4-4.6 (2H, m)     694   0.88 (3H, t, J≈6), 1.0-2.0 (32H, m), 2.6-3.0 (6H, m),           3.7-4.1 (3H, m),                 419  0.81           4.3-4.6 (2H, m)     695   0.97 (3H, t, J=7.3), 1.5-2.0 (6H, m), 2.6-3.0 (6H, m), 3.7 (1H, br,           s),                              237  0.54           3.8-4.1 (2H, m), 4.4-4.6 (2H, m)     696   0.84 (3H, t, J=7.4), 1.21 (3H, d, J≈7), 1.2-2.0 (6H, m),           2.6-2.9 (6H,                     251  0.65           m), 2.8-3.3 (1H, m), 3.8-4.1 (3H, m), 4.3-4.5 (2H, m)     817   0.91 (3H, t), 0.93 (3H, t), 1.1-1.9 (12H, m), 2.0-3.0 (18H, m),           4.08                             375  0.22           (2H, t)     830   0.87 (3H, t), 1.1-1.5 (10H, m), 1.5-2.0 (6H, m), 2.4-2.9 (18H,                                            419  0.23           3.63 (2H, t), 4.09 (2H, t)     837   0.93 (3H, t), 1.0-2.0 (14H, m), 2.0-3.0 (12H, m), 4.11 (3H,                                            318  0.28     839   0.87 (3H, t), 1.1-2.0 (22H, m), 2.4-2.9 (12H, m), 4.12 (2H,                                            274  0.30     850   0.93 (3H, t), 1.06 (6H, t), 1.1-2.0 (8H, m), 2.4-3.0 (12H, m),                                            3068 0.69           (2H, t)     851   0.87 (3H, t), 1.04 (6H, t), 1.2-1.5 (10H, m), 1.5-2.0 (6H, m),           2.5-3.0                          362  0.19           (12H, m), 4.06 (2H, t)     __________________________________________________________________________ 

What is claimed is:
 1. A compound of the formula ##STR301## wherein R is hydroxyl, lower alkoxy, --NH--lower alkylene--OH, --NH--lower alkylene-arylthio, ##STR302## is di-lower alkylamino, morpholino, ##STR303## in which R₉ is hydrogen, lower alkyl or aryl, R₁₀ is hydrogen, lower alkyl, hydroxy-lower alkyl or hydroxy-lower alkoxy-lower alkyl, m is an integer from 4 to 6, n is 2 or 3, R₁ is alkyl or aryl-lower alkyl, R₂ and R₃ are each lower alkyl, and R₄ is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof.
 2. A compound of the formula ##STR304## wherein R is hydroxyl or ##STR305## is di-lower alkylamino, morpholino, ##STR306## in which R₉ is hydrogen, lower alkyl or aryl, R₁₀ is hydrogen, lower alkyl, hydroxy-lower alkyl or hydroxy-lower alkoxy-lower alkyl, m is an integer from 4 to 6, n is 2 or 3, R₁ is alkyl or aryl-lower alkyl, R₂ and R₃ are each lower alkyl, and R₄ is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof. 